Pyridine and pyrimidine based compounds as wnt signaling pathway inhibitors for the treatment of cancer

ABSTRACT

The present invention relates to pyridine and pyrimidine based compounds, pharmaceutical compositions comprising these compounds and their potential use as therapeutic agents for the treatment and/or prevention of cancer.

FIELD OF THE INVENTION

This invention relates to compounds and their use in therapy, inparticular in the treatment, prevention or delay of progression ofcancer.

BACKGROUND TO THE INVENTION

Oncogenic deregulation of the Wnt signalling pathway is a causal factorin the initiation of cancer in a diverse range of tissues including thecolon, breast and liver (see, for example, Barker et al, “Mining the Wntpathway for cancer therapeutics”, Nature Reviews Drug Discovery,December 2006 Vol. 5, 997). There remains a need for effectiveanti-cancer agents, in particular inhibitors of the Wnt signallingpathway.

WO 01/27107 discloses heterocyclic sodium/proton exchange inhibitorswhich are useful in the treatment of cardiovascular disorders. Includedare pyrimidine compounds which are substituted by animidazolylpiperidinyl group.

SUMMARY OF THE INVENTION

According to the present invention, there is provided a compound of theformula (I):

wherein

-   -   W, X and Y are each independently CH, C(R⁴) or N;    -   Z is C(R⁶) or N;    -   R¹ and R² are each independently hydrogen or C₁₋₆ alkyl; or R¹        and R² taken together with the carbon atom to which they are        attached may form a 5- or 6-membered carbocycle or heterocycle,        either of which is optionally substituted with 1, 2, 3, 4 or 5        R^(a);    -   R³ and R⁴ are each independently halo or a group selected from        C₁₋₆ alkyl, C₁₋₆ alkoxy, carbocyclyl and heterocyclyl, any of        which is optionally substituted with 1, 2, 3, 4 or 5 R^(a);    -   when Z is N, R⁵ is R⁷, —C(O)R⁷, —C(O)OR⁷—, —S(O)_(l)R⁷,        —C(O)N(R⁷)R⁶, —C(S)N(R⁷)R⁸—, —S(O)_(l)N(R⁷)R⁸ or heterocyclyl        optionally substituted with 1, 2, 3, 4 or 5 R^(a);    -   when Z is C(R⁶), R⁵ is H, CN, C(O)OH, —C(O)R⁷, —C(O)OR⁷—,        —S(O)_(l)R⁷, —N(R⁶)R⁷, —C(O)N(R⁷)R⁸, —C(S)N(R⁷)R⁸—,        —S(O)_(l)N(R⁷)R⁶, —N(R⁷)C(O)R⁶, —N(R⁷)S(O)_(l)R⁸ or an C₁₋₆        alkyl or heterocyclyl group which is optionally substituted with        1, 2, 3, 4 or 5 R^(a);    -   R⁶ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —OH, R⁵, (CH₂)_(m)R⁵ or        —N(R)R⁸;    -   or R⁵ and R⁶ taken together with the carbon atom to which they        are attached may form a 5- or 6-membered heterocycle which is        optionally substituted with 1, 2, 3, 4 or 5 R^(a);    -   R⁷ and R⁸ are each independently hydrogen or a group selected        from C₁₋₆ alkyl optionally containing 1, 2 or 3 heteroatoms        selected from N, O and S, carbocyclyl and heterocyclyl, any of        which is optionally substituted with 1, 2, 3, 4 or 5 R^(a);    -   or R⁷ and R⁸ may be linked so that, together with the atoms to        which they are attached, they form a 5- or 6-membered        heterocycle which is optionally substituted with 1, 2, 3, 4 or 5        R⁸;    -   each R^(a) is independently selected from halogen,        trifluoromethyl, cyano, oxo, nitro, —OR^(b), —C(O)R⁶, —C(O)OR⁶,        —OC(O)R⁶, —S(O)_(l)R⁶, —N(R^(b))R^(c), —N(R⁶)C(O)R^(c),        —C(O)N(R^(b))R^(c), —S(O)_(l)N(R^(b))R^(c) and R^(d);    -   R^(b) and R^(c) are each independently hydrogen or R^(d);    -   R^(d) is selected from hydrocarbyl (e.g. C₁₋₆alkyl),        carbocyclyl, carbocyclyl-C₁₋₆alkyl, and heterocyclyl, each of        which is optionally substituted with 1, 2, 3, 4 or 5        substituents independently selected from halogen, cyano, amino,        hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy;    -   l is 0, 1 or 2; and    -   m and n are each independently 1, 2 or 3;        or a pharmaceutically acceptable salt, N-oxide or prodrug        thereof.

In a further aspect, the present invention provides a compound of theformula (I):

wherein

-   -   W, X and Y are each independently ═CH—, ═C(R⁴)— or ═N—;    -   Z is C(R⁶) or N;    -   R¹ and R² are each independently hydrogen or C₁₋₆ alkyl; or R¹        and R² taken together with the carbon atom to which they are        attached may form a 5- or 6-membered carbocycle or heterocycle,        either of which is optionally substituted with 1, 2, 3, 4 or 5        R^(a);    -   R³ and R⁴ are each independently halo or a group selected from        C₁₋₆ alkyl, C₁₋₆ alkoxy, carbocyclyl and heterocyclyl, any of        which is optionally substituted with 1, 2, 3, 4 or 5 R^(a);    -   when Z is N, R⁵ is R⁷, —C(O)R⁷, —S(O)_(l)R⁷, —C(O)N(R⁷)R⁸,        —S(O)_(l)N(R⁷)R⁸ or heterocyclyl optionally substituted with 1,        2, 3, 4 or 5 R^(a);    -   when Z is C(R⁶), R⁶ is H, —CN, C(O)OH, —C(O)R⁷, —S(O)_(l)R⁷,        —N(R⁶)R⁷, —C(O)N(R⁷)R⁸, —S(O)_(l)N(R⁷)R⁸, —N(R⁷)C(O)R⁸,        —N(R⁷)S(O)_(l)R⁸ or heterocyclyl optionally substituted with 1,        2, 3, 4 or 5 R^(a);    -   R⁶ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —OH, R⁵ or (CH₂)_(l)R⁶;    -   or R⁵ and R⁶ taken together with the carbon atom to which they        are attached may form a 5- or 6-membered heterocycle which is        optionally substituted with 1, 2, 3, 4 or 5 R^(a);    -   R⁷ and R⁸ are each independently hydrogen or a group selected        from C₁₋₆ alkyl optionally containing 1, 2 or 3 heteroatoms        selected from N, O and S, carbocyclyl and heterocyclyl, any of        which is optionally substituted with 1, 2, 3, 4 or 5 R^(a);    -   each Ra is independently selected from halogen, trifluoromethyl,        cyano, oxo, nitro, —OR^(b), —C(O)R^(b), —C(O)OR^(b),        —OC(O)R^(b), —S(O)_(l)R^(b), —N(R^(b))R^(a), —N(R^(b))C(O)R^(a),        —C(O)N(R^(b))R^(a), —S(O)_(l)N(R^(b))R^(c) and R^(d);    -   R^(b) and R^(c) are each independently hydrogen or R^(d);    -   R^(d) is selected from hydrocarbyl and heterocyclyl, either of        which is optionally substituted with 1, 2, 3, 4 or 5        substituents independently selected from halogen, cyano, amino,        hydroxy, C₁₋₆ alkyl and C₁₋₆ alkoxy;    -   l is 0, 1 or 2; and    -   m and n are each independently 1, 2 or 3;        or a pharmaceutically acceptable salt, N-oxide or prodrug        thereof, for use in the treatment, prevention or delay of        progression of cancer.

The invention also provides a pharmaceutical formulation comprising acompound of formula (I), or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier or excipient.

In a further aspect, the invention relates to the use of a compound offormula (I), or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for the treatment, prevention or delay ofprogression of cancer. A method of treating, preventing or delayingprogression of cancer is also provided, which involves administering atherapeutically effective amount of a compound of the invention to asubject.

Compounds of the invention can exist in different forms, such as freeacids, free bases, esters, N-oxides and other prodrugs, salts andtautomers, for example, and the disclosure includes all variant forms ofthe compounds.

Features, integers, characteristics, compounds, chemical moieties orgroups described in conjunction with a particular aspect, embodiment orexample of the invention are to be understood to be applicable to anyother aspect, embodiment or example described herein unless incompatibletherewith.

DESCRIPTION OF VARIOUS EMBODIMENTS Definitions Hydrocarbyl

The term “hydrocarbyl” as used herein includes reference to moietiesconsisting exclusively of hydrogen and carbon atoms; such a moiety maycomprise an aliphatic and/or an aromatic moiety. The moiety may, forexample, comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms.Examples of hydrocarbyl groups include C₁₋₆ alkyl (e.g. C₁, C₂, C₃ or C₄alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, sec-butylor tert-butyl); C₁₋₆ alkyl substituted by aryl (e.g. benzyl) or bycycloalkyl (e.g cyclopropylmethyl); cycloalkyl (e.g. cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl); alkenyl (e.g. 2-butenyl);alkynyl (e.g. 2-butynyl); aryl (e.g. phenyl, naphthyl or fluorenyl) andthe like.

Alkyl

The terms “alkyl” and “C₁₋₆ alkyl” as used herein include reference to astraight or branched chain alkyl moiety having 1, 2, 3, 4, 5 or 6 carbonatoms. This term includes reference to groups such as methyl, ethyl,propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl ortert-butyl), pentyl, hexyl and the like. In particular, alkyl may have1, 2, 3 or 4 carbon atoms.

Alkenyl

The terms “alkenyl” and “C₂₋₆ alkenyl” as used herein include referenceto a straight or branched chain alkyl moiety having 2, 3, 4, 5 or 6carbon atoms and having, in addition, at least one double bond, ofeither E or Z stereochemistry where applicable. This term includesreference to groups such as ethenyl, 2-propenyl, 1-butenyl, 2-butenyl,3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl and3-hexenyl and the like.

Alkynyl

The terms “alkynyl” and “C₂₋₆ alkynyl” as used herein include referenceto a straight or branched chain alkyl moiety having 2, 3, 4, 5 or 6carbon atoms and having, in addition, at least one triple bond. Thisterm includes reference to groups such as ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 1-hexynyl, 2-hexynyl and 3-hexynyl and the like.

Alkoxy

The terms “alkoxy” and “C₁₋₆ alkoxy” as used herein include reference to—O-alkyl, wherein alkyl is straight or branched chain and comprises 1,2, 3, 4, 5 or 6 carbon atoms. In one class of embodiments, alkoxy has 1,2, 3 or 4 carbon atoms. This term includes reference to groups such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy,hexoxy and the like.

Cycloalkyl

The term “cycloalkyl” as used herein includes reference to an alicyclicmoiety having 3, 4, 5, 6, 7 or 8 carbon atoms. The group may be abridged or polycydic ring system. More often cycloalkyl groups aremonocyclic. This term includes reference to groups such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl andthe like.

Aryl

The term “aryl” as used herein includes reference to an aromatic ringsystem comprising 6, 7, 8, 9 or 10 ring carbon atoms. Aryl is oftenphenyl but may be a polycyclic ring system, having two or more rings, atleast one of which is aromatic. This term includes reference to groupssuch as phenyl, naphthyl and the like.

Carbocyclyl

The term “carbocyclyl” as used herein includes reference to a saturated(e.g. cycloalkyl) or unsaturated (e.g. aryl) ring moiety having 3, 4, 5,6, 7, 8, 9 or 10 ring carbon atoms. In particular, carbocyclyl includesa 3- to 10-membered ring or ring system and, in particular, a 5- or6-membered ring, which may be saturated or unsaturated. A carbocyclicmoiety is, for example, selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl, phenyl,naphthyl, and the like.

Heterocyclyl

The term “heterocyclyl” as used herein includes reference to a saturated(e.g. heterocycloalkyl) or unsaturated (e.g. heteroaryl) heterocyclicring moiety having from 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, at leastone of which is selected from nitrogen, oxygen, phosphorus, silicon andsulphur. In particular, heterocyclyl includes a 3- to 10-membered ringor ring system and more particularly a 5- or 6-membered ring, which maybe saturated or unsaturated.

A heterocyclic moiety is, for example, selected from oxiranyl, azirinyl,1,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl,thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl,2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl,imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl,thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl,pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl,morpholinyl, thiomorpholinyl, especially thiomorpholino, indolizinyl,isoindolyl, 3H-indolyl, indolyl, benzimidazolyl, cumaryl, indazolyl,triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl,tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl,octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl,dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl,quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl,furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl,isochromanyl, chromanyl and the like.

Heterocycloalkyl

The term “heterocycloalkyl” as used herein includes reference to asaturated heterocyclic moiety having 3, 4, 5, 6 or 7 ring carbon atomsand 1, 2, 3, 4 or 5 ring heteroatoms selected from nitrogen, oxygen,phosphorus and sulphur. The group may be a polycyclic ring system butmore often is monocyclic. This term includes reference to groups such asazetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl,pyrazolidinyl, imidazolyl, indolizidinyl, piperazinyl, thiazolidinyl,morpholinyl, thiomorpholinyl, quinolizidinyl and the like.

Heteroaryl

The term “heteroaryl” as used herein includes reference to an aromaticheterocyclic ring system having 5, 6, 7, 8, 9 or 10 ring atoms, at leastone of which is selected from nitrogen, oxygen and sulphur. The groupmay be a polycyclic ring system, having two or more rings, at least oneof which is aromatic, but is more often monocyclic. This term includesreference to groups such as pyrimidinyl, furanyl, benzo[b]thiophenyl,thiophenyl, pyrrolyl, imidazolyl, pyrrolidinyl, pyridinyl,benzo[b]furanyl, pyrazinyl, purinyl, indolyl, benzimidazolyl,quinolinyl, phenothiazinyl, triazinyl, phthalazinyl, 2H-chromenyl,oxazolyl, isoxazolyl, thiazolyl, isoindolyl, indazolyl, purinyl,isoquinolinyl, quinazolinyl, pteridinyl and the like.

Halogen

The term “halogen” as used herein includes reference to F, Cl, Br or I.In a particular, halogen may be F or Cl, of which F is more common.

Substituted

The term “substituted” as used herein in reference to a moiety meansthat one or more, especially up to 5, more especially 1, 2 or 3, of thehydrogen atoms in said moiety are replaced independently of each otherby the corresponding number of the described substituents. The term“optionally substituted” as used herein means substituted orunsubstituted.

It will, of course, be understood that substituents are only atpositions where they are chemically possible, the person skilled in theart being able to decide (either experimentally or theoretically)without inappropriate effort whether a particular substitution ispossible. For example, amino or hydroxy groups with free hydrogen may beunstable if bound to carbon atoms with unsaturated (e.g. olefinic)bonds. Additionally, it will of course be understood that thesubstituents described herein may themselves be substituted by anysubstituent, subject to the aforementioned restriction to appropriatesubstitutions as recognised by the skilled man.

Pharmaceutically Acceptable

The term “pharmaceutically acceptable” as used herein includes referenceto those compounds, materials, compositions, and/or dosage forms whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of human beings or animals without excessivetoxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio. Thisterm includes acceptability for both human and veterinary purposes.

Independently

Where two or more moieties are described as being “each independently”selected from a list of atoms or groups, this means that the moietiesmay be the same or different. The identity of each moiety is thereforeindependent of the identities of the one or more other moieties.

Compounds

The present invention provides compounds of the formula (I) andpharmaceutically acceptable salts, N-oxides and prodrugs thereof

-   -   wherein W, X, Y, Z, R¹, R², R³, R⁵, m and n are as defined        herein.

Various embodiments of the invention are described below. It will beappreciated that the features specified in each embodiment may becombined with other specified features, to provide yet furtherembodiments.

In an embodiment, m and n are each independently selected from 1 or 2.

In an embodiment, m and n are 1.

In an embodiment, one of m and n is 1, and the other is 2.

In an embodiment, m and n are each 2.

In an embodiment, R¹ and R² are each independently hydrogen or methyl;or R¹ and R² taken together with the carbon atom to which they areattached form a 5- or 6-membered heterocycle containing a ringheteroatom selected from 0 and N.

In an embodiment, R¹ and R² are each independently hydrogen or methyl.

In an embodiment, R¹ and R² are each hydrogen.

In an embodiment, X and Y are each independently selected from CH andC(R⁴), and W is selected from CH, C(R⁴) and N.

In an embodiment, X and Y are each CH; and W is CH, C(R⁴) or N.

In an embodiment, W is CH, C(R⁴), or N. In a particular embodiment, W isC(R⁴) or N.

In a further embodiment, W is C(R⁴). Of particular mention are compoundsin which R⁴ is halo, e.g. chloro or bromo.

In an embodiment, the heteroaryl ring shown in Formula (I) contains atleast one ring nitrogen atom in the form of an N-oxide. Suitably, insuch embodiments, it is the nitrogen atom disposed between atoms X and Ythat is in the form of an N-oxide.

In an embodiment, R³ is halo (e.g. chloro or bromo) or a group selectedfrom C₁₋₆ alkyl, aryl and heteroaryl, any of which is optionallysubstituted with 1, 2, 3, 4 or 5 R^(a). By way of example, each R^(a)may be independently selected from halogen, cyano, amino, hydroxy, C₁alkyl and C₁₋₆ alkoxy.

In a further embodiment, R³ is halo (e.g. chloro or bromo) or a groupselected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl, and a 5- or 6-memberedheteroaryl, any of which is optionally substituted with 1, 2, or 3R^(a). By way of example, each Ra may be independently selected fromhalogen, cyano, amino, hydroxy, trifluoromethyl, C₁₋₄ alkyl,NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂, —S(O)_(l)C₁₋₄alkyl (where l is 0, 1 or 2)and C₁₄ alkoxy.

In an embodiment, R³ is halo (e.g. chloro or bromo) or a group selectedfrom C₁₋₆ alkyl (e.g. methyl or ethyl), phenyl, pyrazolyl, triazolyl,oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl andthiophenyl, any of which is optionally substituted with 1, 2, 3, 4 or 5R^(a). By way of example, each R^(a) may be independently selected fromhalogen, cyano, amino, hydroxy, C₁₋₆ alkyl and C₁₋₆ alkoxy. In anembodiment, R³ is halo. In an embodiment, R³ is C₁₋₆ alkoxy.

In an embodiment, R³ is halo (e.g. chloro or bromo) or a group selectedfrom C₁₋₆ alkyl (e.g. methyl or ethyl), C₃₋₆cycloalkyl (e.g.cyclopropyl), phenyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl,pyridinyl, pyridazinyl, pyrimidinyl, and thiophenyl, any of which isoptionally substituted with 1, 2, or 3 R^(a). By way of example, eachR^(a) may be independently selected from halogen, cyano, amino, hydroxy,trifluoromethyl, C₁₋₄ alkyl, NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂,—S(O)_(l)C₁₋₄alkyl (where l is 0, 1 or 2) and C₁₋₄ alkoxy.

In an embodiment, R³ is halo. In an embodiment, R³ is C₁₋₆ alkoxy. In anembodiment, R³ is chloro, bromo or phenyl. In a particular embodiment,R³ is chloro or bromo.

In an embodiment, R⁴ is halo (e.g. chloro or bromo) or a group selectedfrom C₁₋₄ alkyl, C₃₋₆cycloalkyl, phenyl, and a 5- or 6-memberedheteroaryl, any of which is optionally substituted with 1, 2, or 3R^(a). In a further embodiment, R⁴ is halo (e.g. chloro or bromo) or agroup selected from C₁₋₆ alkyl (e.g. methyl or ethyl), C₃₋₆cycloalkyl(e.g. cyclopropyl), phenyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl,pyridinyl, pyridazinyl, pyrimidinyl, and thiophenyl, any of which isoptionally substituted with 1, 2, or 3 R^(a). By way of example, each Ramay be independently selected from halogen, cyano, amino, hydroxy,trifluoromethyl, C₁₋₄ alkyl, NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂,—S(O)_(l)C₁₋₄alkyl (where l is 0, 1 or 2) and C₁₋₄ alkoxy.

In an embodiment, Z is C(R⁶). Of particular mention are compounds inwhich R⁶ is hydrogen, methyl, methoxy or methoxymethyl. In anembodiment, R⁶ is selected from hydrogen, methyl or —N(R⁷)R⁸. In aparticular embodiment, R⁶ is selected from hydrogen, methyl or—NH-phenyl. In a particular embodiment, R⁶ is selected from hydrogen ormethyl. In a further embodiment, R⁶ is hydrogen.

In an embodiment, R⁵ is H, CN, —C(O)OH, —C(O)OR⁷—, —C(O)N(R⁷)R⁶ orheterocyclyl. In another embodiment, R⁵ is —C(O)OH or —CN. In anotherembodiment, R⁵ is CN. In an embodiment, R⁵ is —C(O)N(R⁶)R⁷. Ofparticular mention are compounds in which R⁵ is —C(O)NH₂.

In an embodiment, R⁵ and R⁶ taken together with the carbon atom to whichthey are attached form a heterocycle optionally substituted with 1, 2,3, 4 or 5 R^(a). In a particular embodiment, R⁵ and R⁶ taken togetherwith the carbon atom to which they are attached form a heterocyclecomprising a ring amide group, e.g. oxazolidone or 2-oxopyrrolidine,wherein the heterocycle is optionally substituted with 1, 2, 3, 4 or 5R^(a). By way of example, each R^(a) may be independently selected fromhalogen, cyano, amino, hydroxy, C₁₋₆ alkyl and C₁₋₆ alkoxy.

In an embodiment, R⁵ is not an optionally substituted imidazolyl group.

In a further embodiment, when Z is N, R⁵ is R⁷, —C(O)R⁷, —C(O)OR⁷—,—C(O)N(R⁷)R⁸ or a 5- or 6-membered heterocyclyl optionally substitutedwith 1, 2, 3, 4 or 5 R^(a). In a further embodiment, when Z is N, R⁵ isC₁ alkyl optionally substituted with one or more R^(a), —C(O)R⁷ or—C(O)N(R⁷)R⁸.

In an embodiment, when Z is C(R⁶), R⁵ is H, CN, C(O)OH, —C(O)R⁷,—C(O)OR⁷—, —S(O)_(l)R⁷, —N(R⁷)R⁸, —C(O)N(R⁷)R⁸, —C(S)N(R⁷)R⁸,—S(O)_(l)N(R⁷)R⁸, —N(R⁷)C(O)R⁸, —N(R⁷)S(O)_(l)R⁸ or an C₁₋₆ alkyl,phenyl or 5- or 6-membered heterocyclyl group which is optionallysubstituted with 1, 2, 3, 4 or 5 R^(a).

In a further embodiment, when Z is C(R⁶), R⁵ is H, CN, C(O)OH, —C(O)R⁷,—C(O)OR⁷—, —N(R⁷)R⁸, —C(O)N(R⁷)R⁸, —C(S)N(R⁷)R⁸, —S(O)_(l)N(R⁷)R⁸,—N(R⁷)C(O)R⁸, —N(R⁷)S(O)_(l)R⁸ or an C₁₋₆ alkyl or 5- or 6-memberedheterocyclyl group which is optionally substituted with 1, 2, or 3R^(a).

In a further embodiment, when Z is C(R⁶), R⁵ is CN, C(O)OH, —C(O)R⁷,—C(O)OR⁷—, —N(R⁷)R⁸, —C(O)N(R⁷)R⁸, —C(S)N(R⁷)R⁸—, —N(R⁷)C(O)R⁸, or anC₁₄ alkyl or 5- or 6-membered heterocyclyl group which is optionallysubstituted with 1, 2, or 3 R^(a).

In an embodiment, R⁵ and R⁶ are linked so that, together with the carbonatom to which they are attached, they form a 5- or 6-memberedheterocycle which is optionally substituted with 1, 2, or 3 R^(a). In anembodiment, R⁵ and R⁶ together form a group —C(O)—N(R⁷)—(CH₂)_(q)—,where q is 2 or 3.

In an embodiment, R⁷ and R⁸ are each independently hydrogen or a groupselected from C₁₋₆ alkyl, carbocyclyl and heterocyclyl, any of which isoptionally substituted with 1, 2, 3, 4 or 5 R^(a).

In a further embodiment, R⁷ and R⁸ are each independently hydrogen or agroup selected from C₁₋₆ alkyl, phenyl and 5- or 6-memberedheterocyclyl, any of which is optionally substituted with 1, 2 or 3R^(a). In a further embodiment, at least one of R⁷ and R⁸ is hydrogen.

In an embodiment, R⁷ and R⁸ are connected to a common nitrogen atom andare linked so that, together with the nitrogen atom to which they areattached, they form a 5- or 6-membered heterocycle which is optionallysubstituted with 1, 2, 3, 4 or 5 R^(a). In a particular embodiment, R⁷and R⁸ are linked so that, together with the nitrogen atom to which theyare attached, they form a pyrrolidine, piperidine, piperazine, ormorpholine ring which is optionally substituted with 1, 2 or 3 R^(a).

In an embodiment, each R^(a) group is independently selected fromhalogen, trifluoromethyl, cyano, oxo, nitro, —OR^(b), —C(O)R^(b),—C(O)OR^(b), —OC(O)R^(b), —S(O)_(l)R^(b), —N(R^(b))Rd,—N(R^(b))C(O)R^(c), —C(O)N(R^(b))R^(c), —S(O)_(l)N(R^(b))R^(c) andR^(d). In a further embodiment, each R⁸ group is independently selectedfrom halogen, trifluoromethyl, oxo, —OR^(b), —C(O)R^(b), —S(O)R^(b),—N(R^(b))R^(c), —N(R^(b))C(O)Re, —C(O)N(R^(b))Rd and R^(d).

In an embodiment, R^(d) is selected from C₁₋₆alkyl, C₃₋₆cycloalkyl,phenyl and a 5- or 6-membered heterocyclyl, each of which is optionallysubstituted with 1, 2, 3, 4 or 5 substituents independently selectedfrom halogen, cyano, amino, hydroxy, C₁₋₆ alkyl and C₁₋₆ alkoxy.

In a further embodiment, R^(d) is selected from C₁₋₆alkyl,C₃₋₆cycloalkyl, phenyl and a 5- or 6-membered heterocyclyl, each ofwhich is optionally substituted with 1, 2 or 3 substituentsindependently selected from halogen, cyano, amino, hydroxy, C₁₋₄ alkyland C₁₋₄ alkoxy.

In an embodiment, the compound is of the following formula:

-   -   wherein T is a bond or —CH₂—.

In an embodiment, the compound is of the following formula:

In an embodiment, the compound is of the following formula:

In an embodiment, the compound is of the following formula:

In an embodiment, the compound is of the following formula:

In an embodiment, the compound is of the following formula:

In an embodiment, the compound is of the following formula:

wherein

-   -   W is ═C(R⁴)— or ═N—;    -   Z is C(R⁶);    -   R¹ and R² are each hydrogen;    -   R³ and R⁴ are each independently halo or a group selected from        C₁₋₆ alkyl, C₁₋₆ alkoxy, carbocyclyl and heterocyclyl, any of        which is optionally substituted with 1, 2, 3, 4 or 5 R^(a);    -   R⁵ is H, CN, —C(O)OH, —C(O)N(R⁷)R⁸, or heterocyclyl;    -   R⁶ is hydrogen, C₁₋₆ alkyl, C_(H); alkoxy, —OH, R⁵; or        (CH₂)_(m)R⁵;    -   or R⁵ and R⁶ taken together with the carbon atom to which they        are attached form a 5- or 6-membered heterocycle which is        optionally substituted with 1, 2, 3, 4 or 5 R^(a);    -   R⁷ and R⁸ are each independently hydrogen or a group selected        from C₁₋₆ alkyl optionally containing 1, 2 or 3 heteroatoms        selected from N and O, carbocyclyl and heterocyclyl;    -   each R^(d) is independently selected from halogen,        trifluoromethyl, cyano, oxo, nitro, —OR^(b), —C(O)R^(b),        —C(O)OR^(b), —OC(O)R^(b), —S(O)_(l)R^(b), —N(R^(b))R^(c),        —N(R^(b))C(O)R^(c), —C(O)N(R^(b))R^(o), —S(O)_(l)N(R^(b))R^(c)        and R^(d);    -   R^(d) and R^(c) are each independently hydrogen or R^(d);    -   R^(d) is selected from hydrocarbyl and heterocyclyl, either of        which is optionally substituted with 1, 2, 3, 4 or 5        substituents independently selected from halogen, cyano, amino,        hydroxy, C₁₋₆ alkyl and C₁₋₆ alkoxy;    -   l is 0, 1 or 2; and    -   m and n are each independently 1 or 2;    -   or a pharmaceutically acceptable salt, N-oxide or prodrug        thereof.

In a further aspect, the present invention provides any one of thecompounds listed in the accompanying examples.

Compounds of the invention may be in the form of pharmaceuticallyacceptable salts. The pharmaceutically acceptable salts of the presentdisclosure can be synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts maybe found in Remington's Pharmaceutical Sciences, 17^(th) ed., MackPublishing Company, Easton, Pa., US, 1985, p. 1418, the disclosure ofwhich is hereby incorporated by reference; see also Stahl et al, Eds,“Handbook of Pharmaceutical Salts Properties Selection and Use”, VerlagHelvetica Chimica Acta and Wiley-VCH, 2002.

The invention thus includes pharmaceutically-acceptable salts of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof, for example the conventional non-toxic saltsor the quaternary ammonium salts which are formed, e.g. from inorganicor organic acids or bases. Examples of such acid addition salts includeacetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base saltsinclude ammonium salts, alkali metal salts such as sodium and potassiumsalts, alkaline earth metal salts such as calcium and magnesium salts,salts with organic bases such as dicyclohexylamine salts,N-methyl-D-glucamine, and salts with amino acids such as arginine,lysine, and so forth. Also, the basic nitrogen-containing groups may bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethyl bromidesand others.

The invention includes prodrugs for the active pharmaceutical species ofthe invention, for example in which one or more functional groups areprotected or derivatised but can be converted in vivo to the functionalgroup, as in the case of esters of carboxylic acids convertible in vivoto the free acid, or in the case of protected amines, to the free aminogroup. The term “prodrug,” as used herein, represents in particularcompounds which are rapidly transformed in vivo to the parent compound,for example, by hydrolysis in blood. A thorough discussion is providedin T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, Edward B. Roche, ed., BioreversibleCarriers in Drug Design, American Pharmaceutical Association andPergamon Press, 1987; H Bundgaard, ed, Design of Prodrugs, Elsevier,1985; and Judkins, et al. Synthetic Communications, 26(23), 4351-4367(1996), each of which is incorporated herein by reference.

Prodrugs therefore include drugs having a functional group which hasbeen transformed into a reversible derivative thereof. Typically, suchprodrugs are transformed to the active drug by hydrolysis. Examples ofsuch groups include carboxylic groups (reversible derivatives includingesters, e.g. acyloxyalkyl esters and amides), alcohol groups (reversiblederivatives including sulfates, phosphates and carboxylic acid esters),amine groups (reversible derivatives including amides, carbamates,imines and enamines) and carbonyl groups, e.g. aldehyde and ketonegroups (reversible derivatives including imines, oximes, acetals/ketals,enol esters, oxazolidines and thiazoxolidines).

Prodrugs also include compounds convertible to the active drug by anoxidative or reductive reaction. As examples of oxidative activation maybe mentioned N- and O-dealkylation, oxidative deamination, N-oxidationand epoxidation. As examples of reductive activation may be mentionedazo reduction, sulfoxide reduction, disulfide reduction, bioreductivealkylation and nitro reduction.

Also to be mentioned as metabolic activations of prodrugs are nucleotideactivation, phosphorylation activation and decarboxylation activation.For additional information, see “The Organic Chemistry of Drug Designand Drug Action”, R B Silverman (particularly Chapter 8, pages 497 to546), incorporated herein by reference.

The use of protecting groups is fully described in ‘Protective Groups inOrganic Chemistry’, edited by J W F McOmie, Plenum Press (1973), and‘Protective Groups in Organic Synthesis’, 2^(nd) edition, T W Greene & PG M Wutz, Wiley-Interscience (1991).

Thus, it will be appreciated by those skilled in the art that, althoughprotected derivatives of compounds of the disclosure may not possesspharmacological activity as such, they may be administered, for exampleparenterally or orally, and thereafter metabolised in the body to formcompounds of the invention which are pharmacologically active. Suchderivatives are therefore examples of “prodrugs”. All prodrugs of thedescribed compounds are included within the scope of the disclosure.

Some groups mentioned herein (especially those containing heteroatomsand conjugated bonds) may exist in tautomeric forms and all thesetautomers are included in the scope of the disclosure. More generally,many species may exist in equilibrium, as for example in the case oforganic acids and their counterpart anions; a reference herein to aspecies accordingly includes reference to all equilibrium forms thereof.

The compounds of the disclosure may also contain one or more asymmetriccarbon atoms and may therefore exhibit optical and/ordiastereoisomerism. All diastereoisomers may be separated usingconventional techniques, e.g. chromatography or fractionalcrystallisation. The various stereoisomers may be isolated by separationof a racemic or other mixture of the compounds using conventional, e.g.fractional crystallisation or HPLC, techniques. Alternatively thedesired optical isomers may be made by reaction of the appropriateoptically active starting materials under conditions which will notcause racemisation or epimerisation, or by derivatisation, for examplewith a homochiral acid followed by separation of the diastereomericderivatives by conventional means (e.g. HPLC, chromatography oversilica). All stereoisomers are included within the scope of thedisclosure. Where a single enantiomer or diasteromer is disclosed, thedisclosure also covers the other enantiomers or diastereomers, and alsoracemates; in this regard, particular reference is made to the specificcompounds listed herein.

Geometric isomers may also exist in the compounds of the presentdisclosure. The present disclosure contemplates the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon-carbon double bond and designates suchisomers as of the Z or E configuration, wherein the term “Z” representssubstituents on the same side of the carbon-carbon double bond and theterm “E” represents substituents on opposite sides of the carbon-carbondouble bond.

The disclosure therefore includes all variant forms of the definedcompounds, for example any tautomer or any pharmaceutically acceptablesalt, ester, acid or other variant of the defined compounds and theirtautomers as well as substances which, upon administration, are capableof providing directly or indirectly a compound as defined above orproviding a species which is capable of existing in equilibrium withsuch a compound.

Synthesis

A compound of the invention may be prepared according to the processesdescribed herein. It will be understood that these processes are solelyfor the purpose of illustrating the invention and should not beconstrued as limiting. A process utilising similar or analogous reagentsand/or conditions known to one skilled in the art may also be used toobtain a compound of the invention.

Any mixtures of final products or intermediates obtained can beseparated on the basis of the physico-chemical differences of theconstituents, in a known manner, into the pure final products orintermediates, for example by chromatography, distillation, fractionalcrystallisation, or by the formation of a salt if appropriate orpossible under the circumstances.

Administration & Pharmaceutical Formulations

The compounds of the invention will normally be administered orally,intravenously, subcutaneously, buccally, rectally, dermally, nasally,tracheally, bronchially, by any other parenteral route, as an oral ornasal spray or via inhalation, The compounds may be administered in theform of pharmaceutical preparations comprising prodrug or activecompound either as a free compound or, for example, a pharmaceuticallyacceptable non-toxic organic or inorganic acid or base addition salt, ina pharmaceutically acceptable dosage form. Depending upon the disorderand patient to be treated and the route of administration, thecompositions may be administered at varying doses.

Typically, therefore, the pharmaceutical compounds of the invention maybe administered orally or parenterally (“parenterally” as used herein,refers to modes of administration which include intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous andintraarticular injection and infusion) to a host. In the case of largeranimals, such as humans, the compounds may be administered alone or ascompositions in combination with pharmaceutically acceptable diluents,excipients or carriers.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions, and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required for toachieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved.

In certain embodiments, an appropriate dosage level will generally beabout 0.01 to 500 mg per kg patient body weight per day which can beadministered in single or multiple doses. In a particular embodiment,the dosage level is about 0.1 to about 250 mg/kg per day; morepreferably about 0.5 to about 100 mg/kg per day. A suitable dosage levelmay be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day,or about 0.1 to 50 mg/kg per day. Within this range the dosage may be0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration,the compositions may be provided in the form of tablets containing 1.0to 1000 milligrams of the active ingredient, particularly 1.0, 5.0,10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0,400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. The compounds may be administered on a regimen of1 to 4 times per day, e.g. once or twice per day. The dosage regimen maybe adjusted to provide the optimal therapeutic response.

According to a further aspect of the invention there is thus provided apharmaceutical composition including a compound of the invention, inadmixture with a pharmaceutically acceptable adjuvant, diluent orcarrier.

Pharmaceutical compositions of this invention for parenteral injectionsuitably comprise pharmaceutically acceptable sterile aqueous ornonaqueous solutions, dispersions, suspensions or emulsions as well assterile powders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), and suitable mixtures thereof, vegetable oils(such as olive oil) and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservative,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben, chlorobutanolor phenol sorbic acid. It may also be desirable to include isotonicagents such as sugars or sodium chloride, for example. Prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents (for example aluminum monostearate and gelatin)which delay absorption.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are suitably made by forming microencapsulematrices of the drug in biodegradable polymers, for examplepolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(an hydrides). Depot injectableformulations may also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues. The injectableformulations can be sterilized, for example, by filtration through abacterial-retaining filter or by incorporating sterilizing agents in theform of sterile solid compositions which can be dissolved or dispersedin sterile water or other sterile injectable media just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound is typically mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier such as sodium citrate or dicalciumphosphate and/or one or more: a) fillers or extenders such as starches,lactose, sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents. Solid compositions of a similar type mayalso be employed as fillers in soft and hard-filled gelatin capsulesusing such excipients as lactose or milk sugar as well as high molecularweight polyethylene glycol, for example.

Suitably, oral formulations contain a dissolution aid. The dissolutionaid is not limited as to its identity so long as it is pharmaceuticallyacceptable. Examples include nonionic surface active agents, such assucrose fatty acid esters, glycerol fatty acid esters, sorbitan fattyacid esters (e.g. sorbitan trioleate), polyethylene glycol,polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fattyacid esters, polyoxyethylene alkyl ethers, methoxypolyoxyethylene alkylethers, polyoxyethylene alkylphenyl ethers, polyethylene glycol fattyacid esters, polyoxyethylene alkylamines, polyoxyethylene alkylthioethers, polyoxyethylene polyoxypropylene copolymers, polyoxyethyleneglycerol fatty acid esters, pentaerythritol fatty acid esters, propyleneglycol monofatty acid esters, polyoxyethylene propylene glycol monofattyacid esters, polyoxyethylene sorbitol fatty acid esters, fatty acidalkylolamides, and alkylamine oxides; bile acid and salts thereof (e.g.chenodeoxycholic acid, cholic acid, deoxycholic acid, dehydrocholic acidand salts thereof, and glycine or taurine conjugate thereof); ionicsurface active agents, such as sodium laurylsulfate, fatty acid soaps,alkylsulfonates, alkyiphosphates, ether phosphates, fatty acid salts ofbasic amino acids; triethanolamine soap, and alkyl quaternary ammoniumsalts; and amphoteric surface active agents, such as betaines andaminocarboxylic acid salts.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, and/or indelayed fashion. Examples of embedding compositions include polymericsubstances and waxes.

The active compounds may also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

The active compounds may be in finely divided form, for example they maybe micronised.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as water or other solvents,solubilizing agents and emulsifiers such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide,oils (in particular, cottonseed, groundnut, corn, germ, olive, castor,and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan and mixtures thereof. Besidesinert diluents, the oral compositions may also include adjuvants such aswetting agents, emulsifying and suspending agents, sweetening, flavoringand perfuming agents. Suspensions, in addition to the active compounds,may contain suspending agents such as ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanthand mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolisable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilisers, preservatives,excipients and the like. The preferred lipids are the phospholipids andthe phosphatidyl cholines (lecithins), both natural and synthetic.

Methods to form liposomes are known in the art, for example, Prescott,Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.(1976), p 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which maybe required. Ophthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Use

Compounds of the invention may be useful in the therapy of a variety ofdiseases and conditions. The subject of said therapy may be a human oran animal. Compounds of the invention may exhibit desirable potency,selectivity and microsomal stability.

In particular, compounds of the invention may be useful in the treatmentor prevention of cancer, such as cancer of the colon, breast or liver.

The following Examples illustrate the invention.

General Synthesis

Example compounds were prepared according to the following reactionschemes.

A 3-step procedure consisting of coupling of N-Boc-isonipecotic acidwith a series of amines utilising HATU as the coupling reagent.Deprotection of the resultant piperidine under acidic conditions,followed by microwave mediated S_(N)Ar coupling furnished amideanalogues A in good yield.

Both 4-chloropyridine and 3,4-dichioropyridine were commerciallyavailable as their hydrochloride salts. The reaction was carried out inwater using an excess of isonipecotamide, leading to excellentconversion into the desired products B & C. The products were found tocrystallise upon cooling the reaction mixture to 0° C.

Amides of the piperidine were first synthesised then coupled to thepyridine fragment. Thus, 1-Boc-4-aminopiperidine was coupled withcarboxylic acids to furnish amides. N-deprotection generated freepiperidines, which underwent S_(N)Ar coupling with3,4,5-trichloropyridine to give analogues D.

The intermediate 4-chloro-3,5-dimethylpyridine was synthesised by theselective chlorination of 3,5-lutidine as reported by Wurster et al (J.Med. Chem. 2006, 49, 6351):

The intermediate 4-chloro-3-methylpyridine was commercially available asits hydrochloride salt.

The pyridines were then coupled to isonipecotamide under aqueousconditions proceeded to furnish analogues E and F in good yield.

Oxidation of the pyridine ring may be achieved using the conditionsdeveloped by Caron et al (Tetrahedron Lett. 2000, 41, 2299) for theoxidation of electron deficient pyridines. The highly reactive oxidisingagent pertrifluoroacetic acid is generated in-situ from hydrogenperoxide-urea complex and trifluoroacetic anhydride.

N-Boc-piperazine was coupled to benzoic acid to furnish the amide whichwas subsequently deprotected and coupled to 3,4,5-trichioropyridine togive H. Similarly 3,4,5-trichloropyridine has been coupled tocommercially available N-acetyl, N-methyl and N-ethyl piperazines tofurnish compounds I, J, K respectively.

This scheme was used to synthesise amide analogues derived fromethylenediamine. The tert-butoxycarbonyl protecting group was thermallyremoved during the coupling reaction, leading to bis-coupled product L.

Carboxybenzyl derivative M was synthesised according to the schemebelow, however attempts at deprotection via hydrogenation led tohydrogenation of the chloride groups, to furnish N.

To this end, the Lewis acid mediated cleavage conditions as reported byStammer et al (J. Chem. Soc., Chem. Comm. 1979, 495) were used toselectively cleave the protecting group using trimethylsilyl iodide tofurnish O in good yield.

Compound O was then subjected to reductive amination utilising a diverseset of aldehydes to furnish further analogues P where stoichiometricamounts of aldehyde were employed or Q when an excess of aldehyde wasused.

A series of analogues of the primary amide functionality weresynthesised by conventional methods. Thus, treatment of the primaryamide with Lawesson's reagent furnished the thioamide R, whilsttreatment with vinylene carbonate furished oxazolone S. Thioamide Rcould be further converted into thiazole T upon treatment withchloroacetaldehyde.

Coupling of 3,4,5-trichloropyridine with 4-cyanopiperidine furnishednitrile analogue U which underwent hydrolysis under acidic conditions toyield carboxylic acid V.

3,4,5-trichloropyridine and 3,5-dibromo-4-chloropyridine were coupledwith 3-cyanopyrrolidine to furnish the nitrile intermediates which couldbe hydrolysed to yield the amide analogues W. The two enantiomeric formsof W could be separated by chiral hplc.

Similarly the ethylene diamine based amide analogues Y could besynthesised by coupling of the intermediate pyrrolidine with3,4,5-trihalo-pyridines.

5-Halopyrimidine analogues Z were synthesised by halogenation of4-pyrimidone followed by coupling with the required cyclic amine.

A more robust route was also established in which the 2-chloropyrimidine intermediate was first synthesised and then subjected tohydrogenolysis. The intermediate 5-bromopyrimidine also underwent Suzukireaction to furnish aryl analogues AA.

Similarly, Suzuki reaction with aryl and heteroaryl boronic acids and5-bromopyridine analogue furnished aryl analogues BB in excellent yield.

In the same way, 3-halo-5-aryl pyridine analogues CC were prepared fromthe dichloro and dibromo-pyridines taking care to avoid double coupling.By using an excess of the boronic acids the double Suzuki reaction tofurnish only the bis-aryl analogues DD could also be performedsuccessfully.

Intermediate 1: tert-butyl-4-(methylcarbamoyl)piperidine-1-carboxylate 1

General Procedure a

To a solution of N-Boc-isonipecotic acid (0.20 g, 0.86 mmol) and HATU(0.43 g, 1.1 mmol) in DMF (4 mL) was added DIPEA (0.76 mL, 4.4 mmol).After stirring the solution for 5 min, methylamine hydrochloride (76 mg,1.1 mmol) was added. After allowing the solution to stir for a further16 h, it was poured into a 1 M solution of sodium hydroxide (50 mL) andextracted with EtOAc (2×50 mL). The combined organic extracts werewashed with water (50 mL), 1 M hydrochloric acid (50 mL), water (50 mL)and brine (50 mL). The organic phase was dried (MgSO₄) and the solventwas evaporated under reduced pressure to yield the title compound as apale yellow oil (69 mg, 33%), υ_(max) (CHCl₃)/cm⁻¹ 3009, 2932, 1677,1522, 1429, 1279, 1166; m/z (ESI) C₁₂H₂₂N₂NaO₃ requires 265.1523, found[M+Na]⁺ 265.1525.

Intermediate 2: tert-butyl-4-(dimethylcarbamoyl)piperidine-1-carboxylate2

General procedure A was followed using N-Boc-isonipecotic acid (0.20 g,0.86 mmol), HATU (0.43 g, 1.1 mmol), DIPEA (0.76 mL, 4.4 mmol),dimethylamine hydrochloride (92 mg, 1.1 mmol) and DMF (4 mL) to furnishthe title compound as a pale brown oil (156 mg, 70%), υ_(max)(CHCl₃)/cm⁻¹ 3020, 2861, 1684, 1631, 1417, 1367, 1151, 1030; m/z (ESI)C₁₃H₂₄N₂NaO₃ requires 279.1679, found [M+Na]⁺ 279.1677.

Intermediate 3:tert-butyl-4-(2-(tert-butoxycarbonylamino)ethylcarbamoyl)piperidine-1-carboxylate3

General procedure A was followed using N-Boc-isonipecotic acid (0.20 g,0.86 mmol), HATU (0.43 g, 1.1 mmol), DIPEA (0.76 mL, 4.4 mmol),N-Boc-ethylenediamine (0.18 g, 1.1 mmol) and DMF (4 mL) to furnish thetitle compound as a beige solid (311 mg, 96%), m.p. 172-174° C.; υ_(max)(CHCl₃)/cm⁻¹ 3022, 2981, 1684, 1671, 1507, 1367, 1241, 1165; m/z (ESI)C₁₈H₃₃N₃NaO₅ requires 394.2312, found [M+Na]⁺ 394.2310.

Intermediate 4:tert-butyl-4-(2-(benzyloxycarbonylamino)ethylcarbamoyl)piperidine-1-carboxylate4

General procedure A was followed using N-Boc-isonipecotic acid (0.10 g,0.44 mmol), HATU (0.22 g, 0.57 mmol), DIPEA (0.38 mL, 2.2 mmol),N-Cbz-ethylenediamine (0.11 g, 0.57 mmol) and DMF (2 mL) to furnish thetitle compound as a yellow wax (170 mg, 96%), υ_(max) (CHCl₃)/cm⁻¹ 3361,3024, 2943, 1713, 1683, 1519, 1428, 1236, 1166; m/z (ESI) C₂₁H₃₂N₃O₅requires 406.2337, found [M+H]⁺ 406.2330.

Intermediate 5: N-methylpiperidine-4-carboxamide 5

General Procedure B

To a solution of tert-butyl-4-(methylcarbamoyl)piperidine-1-carboxylate1 (68 mg, 0.28 mmol) in MeOH (2 mL), cooled to 0° C., was added a 4 Msolution of hydrogen chloride in 1,4-dioxane (2 mL). After stirring for15 min, the solution was allowed to warm to room temperature and afterstirring for a further period of further 3 h, the solvent was removedunder reduced pressure. The crude product was purified by chromatographyon a SCX-2 cartridge (MeOH followed by 0.5 M NH₃ in MeOH) to furnish thetitle compound as a colourless oil (41 mg, 99%), υ_(max)(CHCl₃)/cm⁻¹3008, 2948, 1663, 1525, 1227, 1199; m/z (ESI) C₇H₁₅N₂Orequires 143.1179, found [M+H]⁺143.1178.

Intermediate 6: N,N-dimethylpiperidine-4-carboxamide 6

General procedure B was followed usingtert-butyl-4-(dimethylcarbamoyl)piperidine-1-carboxylate 2 (0.16 g, 0.60mmol), MeOH (2.5 mL) and a 4 M solution of hydrogen chloride in1,4-dioxane (2.5 mL) to furnish the title compound as a pale yellow oil(67 mg, 71%), υ_(max) (CHCl₃)/cm⁻¹ 3003, 2947, 1625, 1497, 1401, 1320,1240, 1137, 1105; m/z (ESI) C₈H₇N₂O requires 157.1335, found [M+H]⁺157.1338.

Intermediate 7: N-(2-aminoethyl)piperidine-4-carboxamide 7

General procedure B was followedtert-butyl-4-(2-(tert-butoxycarbonylamino)ethylcarbamoyl)piperidine-1-carboxylate 3 (0.31 g, 0.83 mmol), MeOH (5 mL)and a 4 M solution of hydrogen chloride in 1,4-dioxane (5 mL) to furnishthe title compound as a colourless oil (109 mg, 76%), υ_(max) cm⁻¹ 3284,3940, 1647, 1550, 1139, 1035; m/z (ESI) C₈H₁₈N₃O requires 172.1444,found [M+H]⁺ 172.1445.

Intermediate 8: benzyl 2-(piperidine-4-carboxamido)ethylcarbamate 8

General procedure B was followedtert-butyl-4-(2(benzyloxycarbonylamino)ethylcarbamoyl)piperidine-1-carboxylate 4 (0.19 g, 0.46 mmol), MeOH (3 mL) and a 4 Msolution of hydrogen chloride in 1,4-dioxane (3 mL) to furnish the titlecompound as a colourless oil (108 mg, 76%), m.p. 165-167° C.; υ_(max)(CHCl₃)/cm⁻ 3013, 2946, 1713, 1661, 1519, 1260, 1226, 1140, 1014; m/z(ESI) C₁₆H₂₄N₃O₃ requires 306.1812, found [MH]⁺ 306.1808.

Intermediate 9: tert-butyl 4-benzoylpiperazine-1-carboxylate 9

General procedure A was followed using 1-Boc-piperazine (50 mg, 0.27mmol), benzoic acid (43 mg, 0.35 mmol), HATU (0.14 g, 0.35 mmol), DIPEA(0.23 ml 1.4 mmol) and DMF (2 mL) to furnish the title compound as abeige solid (75 mg, 98%), m.p. 105-107° C.; υ_(max) (CHCl₃)/cm⁻¹ 3011,2930, 2866, 1691, 1626, 1421, 1249, 1158; m/z (ESI) C₁₆H₂₂N₂NaO₃requires 313.1523, found [M+Na]⁺ 313.1528.

Intermediate 10: 4-benzoylpiperazine-1-carboxylate 10

General procedure B was followed using tert-butyl4-benzoylpiperazine-1-carboxylate 9 (75 mg, 0.26 mmol), MeOH (2 mL) anda 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL) to furnish thetitle compound as a colourless oil (47 mg, 96%), υ_(max) (CHCl₃)/cm⁻¹3015, 2954, 1622, 1435, 1290, 1136, 1018; m/z (ESI) C₁₁H₁₅N₂O requires191.1179, found [M+H]⁺ 191.1179.

Intermediate 11:benzyl-2-(1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamido)ethylcarbamate 11

General procedure C (See Example 1) was followed usingbenzyl-2-(piperidine-4-carboxamido)ethylcarbamate 14 (59 mg, 0.19 mmol),3,4,5-trichloropyridine (35 mg, 0.19 mmol), triethylamine (27 μL, 0.58mmol) and NMP (1.5 mL). The crude product was purified by flash columnchromatography on silica gel (hexane/EtOAc, 1:1) to furnish the titlecompound as a white solid (42 mg, 48%), m.p. 147-149° C.; υ_(max)(CHCl₃)/cm⁻¹ 3453, 3009, 2853, 1713, 1668, 1516, 1260, 1147, 1013; m/z(ESI) CH₂₁H₂₅Cl₂N₄O₃ requires 451.1298, found [M+H]⁺ 451.1301.

Intermediate 12: Benzyl4-(piperidine-4-carbonyl)piperazine-1-carboxylate 12

General procedure A was followed using N-Boc-isonipecotic acid (0.25 g,1.1 mmol), HATU (0.46 g, 1.2 mmol), DIPEA (0.57 mL, 3.3 mmol),1-Cbz-piperazine (0.21 mL, 1.1 mmol) and DMF (5 mL) to furnish theintermediate compoundbenzyl-4-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)piperazine-1-carboxylate as a white solid (339 mg, 72%), υ_(max)(CHCl₃)/cm⁻¹ 3014, 2863, 1688, 1644, 1427, 1367, 1205, 1168.

General procedure B was subsequently followed usingbenzyl-4-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)piperazine-1-carboxylate (330 mg), MeOH (10 mL) and a 4 M solution ofhydrogen chloride in 1,4-dioxane (10 mL) to furnish the title compound12 as a white solid (120 mg, 46%), υ_(max) (CHCl₃)/cm⁻¹ 3016, 2949,1699, 1639, 1431, 1250, 1227, 1125, 1019; m/z (ESI) C₁₈H₂₆N₃O₃ requires332.1969, found [M+H]⁺ 332.1968.

Intermediate 13:benzyl-4-(1-(3,5-dichloropyridin-4-yl)piperidine-4-carbonyl)piperazine-1-carboxylate13

General procedure C (See Example 1) was followed usingbenzyl-4-(piperidine-4-carbonyl)piperazine-1-carboxylate 12 (0.11 g,0.33 mmol), 3,4,5-trichloropyridine (61 mg, 0.33 mmol), NMP (2.5 mL) andtriethylamine (93 μL, 0.66 mmol). The crude product was purified byflash column chromatography on silica gel (hexane, EtOAc, 1:1) tofurnish the title compound 13 as a white solid (58 mg, 36%), υ_(max)(CHCl₃)/cm⁻¹ 3023, 1699, 1635, 1559, 1432, 1285, 1232, 1015; m/z (ESI)C₂₃H₂₇Cl₂N₄O₃ requires 477.1455, found [M+H]⁺ 477.1457.

Intermediate 14:(R,S)-1-(3,5-dichloropyridin-4-yl)pyrrolidine-3-carbonitrile 14

i) To a solution of (R,S)—N-Boc-3-cyanopyrrolidine (0.25 g, 1.3 mmol) inMeOH (5 mL) was added hydrogen chloride (5 mL of a 4 M solution indioxane) and the mixture was stirred for 3 hours, after which time thesolvent was removed under reduced pressure. The crude product waspurified on an SCX-2 cartridge (MeOH followed by 0.5 M NH₃ in MeOH) tofurnish (R,S)-3-cyanopyrrolidine as a colourless oil (136 mg, 100%).

ii) To a solution of (R,S)-3-cyanopyrrolidine (0.12 g, 1.3 mmol) and3,4,5-trichloropyridine (0.23 g, 1.3 mmol), in NMP (8 mL) was addedtriethylamine (0.36 mL, 2.6 mmol). The mixture was heated at 220° C. for60 min in a microwave reactor, poured into a saturated solution ofsodium hydrogen carbonate (50 mL) and extracted with EtOAc (2×100 mL).The combined organic extracts were washed with water (50 mL), brine (50mL), dried (MgSO₄) and concentrated under reduced pressure. The crudeproduct was purified by flash column chromatography on silica gel(CH₂Cl₂, MeOH, 99:1) to furnish the title compound as a colourless oil(155 mg, 50%), υ_(max) (CHCl₃)/cm⁻¹ 3053, 2245, 1558, 1468, 1402; m/z(ESI) C₁₀H₁₀Cl₂N₃ requires 242.0246 found [M+H]⁺ 242.0249.

Intermediate 15:(R,S)-3-(2-benzyloxycarbonylamino-ethylcarbamoyl)pyrrolidine-1-carboxylicacid tert-butyl ester 15

To a solution of (R,S)-1-Boc-pyrrolidine-3-carboxylic acid (0.22 g, 2.2mmol), N—Z-ethylenediamine hydrochloride (0.50 g, 2.2 mmol) and HATU(0.82 g, 2.2 mmol) in DMF (15 mL) was added DIPEA (1.9 mL, 11 mmol) andthe solution was stirred at r.t. for 16 h. The mixture was poured into asaturated solution of sodium hydrogen carbonate (50 mL) and extractedwith EtOAc (2×40 mL). The combined organic extracts were washed withwater (50 mL), a saturated solution of citric acid (50 mL), water (50mL) and brine (50 mL), dried (MgSO₄) and concentrated under reducedpressure to furnish the title compound 15 as a colourless oil (0.43 g,100%). This compound was used directly, without further purification.

Intermediate 16: {2-[(pyrrolidine-3-carbonyl)-amino]-ethyl}-carbamicacid benzyl ester 16

To a solution of(R,S)-3-(2-benzyloxycarbonylamino-ethylcarbamoyl)pyrrolidine-1-carboxylicacid tert-butyl ester 15 (430 mg, 1.10 mmol) in MeOH (5 mL) was added a4 M solution of hydrogen chloride in 1,4-dioxane (5 mL). After stirringfor 2 h, the mixture was concentrated under reduced pressure and thecrude product was purified on an SCX-2 cartridge (MeOH followed by 0.5 MNH₃ in MeOH) to furnish the title compound as a white solid (260 mg,81%), m.p. 129-131° C.; υ_(max) (CHCl₃)/cm⁻¹ 3451, 3014, 1714, 1663,1517, 1227; m/z (ESI) C₁₅H₂₂N₃O₃ requires 292.1656, found [M+H]⁺292.1654.

Intermediate 17:(R,S)-(2-{[1-(3,5-dichloro-pyridin-4-yl)-pyrrolidine-3-carbonyl]-amino}-ethyl)-carbamicacid benzyl ester 17

General procedure C was followed using 3,4,5-trichloropyridine (50 mg,0.27 mmol), (R,S)-{2-[(pyrrolidine-3-carbonyl)-amino]ethyl}-carbamicacid benzyl ester 16 (80 mg, 0.27 mmol), NMP (3 mL) and triethylamine(0.11 mL, 0.82 mmol). The crude product was purified by flash columnchromatography on silica gel (CH₂Cl₂, MeOH, 99:1) to furnish the titlecompound as a white solid (61 mg, 51%), m.p. 148-150° C.; υ_(max)(CHCl₃)/cm⁻¹ 3028, 1716, 1668, 1515, 1464, 1221; m/z (ESI) C₂₀H₂₃Cl₂N₄O₃requires 437.1141, found [M+H]⁺ 437.1142.

Intermediate 18: 3,5-dibromo-4-chloropyridine 18

To a solution of 4-(1H)-pyridone (0.95 g, 10 mmol) and potassiumhydroxide (1.1 g, 20 mmol) in water (20 mL) cooled to 0° C. was addedbromine (3.2 g, 20 mmol). After stirring at this temperature for 75 min,the mixture was filtered and the cake was washed with washed with coldwater (3×50 mL) and hexane (3×20 mL) to furnish3,5-dibromo-4-(1H)-pyridone as a white solid (2.09 g, 83%).

To 3,5-dibromo-4-(1H)-pyridone (0.25 g, 1.0 mmol) was added POCl₃ (2 mL)and the mixture was heated at 100° C. for 2 h. The mixture was pouredinto ice/water (25 g) and basified by the addition of a saturatedsolution of sodium hydrogen carbonate. The mixture was extracted withCH₂Cl₂ (2×20 mL), the combined organic extracts were washed with brine(25 mL), dried (MgSO₄) and concentrated under reduced pressure tofurnish the title compound as a white solid (275 mg, 100%), m.p.101-103° C.; m/z 272 (100%, [M+H]⁺);

Intermediate 19:(R,S)-(2-{[1-(3,5-dibromo-pyridin-4-yl)-pyrrolidine-3-carbonyl]-amino}-ethyl)-carb-amicacid benzyl ester 19

General procedure C (See Example 1) was followed using3,5-dibromo-4-chloropyridine 18 (74 mg, 0.27 mmol),(R,S)-3-(2-benzyloxycarbonylamino-ethylcarbamoyl)pyrrolidine-1-carboxylicacid tert-butyl ester 16 (80 mg, 0.27 mmol), NMP (3 mL) andtriethylamine (0.11 mL, 0.82 mmol). The crude product was purified byflash column chromatography on silica gel (CH₂Cl₂, MeOH, 99:1) tofurnish the title compound as a white solid (86 mg, 60%), m.p. 132-134°C.; υ_(max) (CHCl₃)/cm-1 3029, 3024, 1729, 1665, 1518, 1446, 1249, 1229,1046, 1016; m/z (ESI) C₂₀H₂₂Br₂N₄NaO₃ requires 546.9951, found [M+Na]⁺546.9946.

Intermediate 20: 4,5-dichloropyrimidine hydrochloride 20

Chlorine was bubbled through a solution of 4-pyrimidone (1.9 g, 20 mmol)in glacial acetic acid (20 mL) for 1 h and the reaction mixture wasstirred for a further 2 h. Chlorine was bubbled through the solution fora further 15 min and the mixture stirred for a further 90 min. Themixture was filtered and the cake was washed with hexane (3×25 mL) tofurnish the title compound as a white solid (2.28 g).

A suspension of 5-chloropyrimidine hydrochloride (1.0 g, 6.0 mmol) inphosphorous oxychloride (4 mL) was heated at 90° C. for 90 min thencooled to room temperature and filtered. The crude product was purifiedby sublimation under reduced pressure to furnish the title compound 20as a crystalline white solid (273 mg). This compound was unstable to airand was used immediately in the next step.

Intermediate 21: 5-bromo-4-chloropyrimidine hydrochloride 21

A solution of bromine (1.0 mL, 20 mmol) in glacial acetic acid (10 mL)was added over 15 min via cannula to a solution of 4-pyrimidone (1.9 g,20 mmol) in glacial acetic acid (20 mL). After stirring for 5 h, themixture was filtered and the cake was washed with hexane (2×20 mL) tofurnish the title compound as a white solid (1.52 g).

A suspension of 5-bromopyrimidone hydrobromide (1.0 g, 3.9 mmol) inphosphorous oxychloride (4 mL) was heated at 90° C. for 1 h then cooled0° C. The mixture was filtered, washed with POCl₃ (2×2 mL) to furnishthe title compound as a cream solid (388 mg). This compound was unstableto air and was used immediately in the next step.

Intermediate 22: 4-chloro-5-methylpyrimidine hydrochloride 22

To a suspension of 4-hydroxy-2-mercapto-5-methylpyrimidine (1.0 g, 7.0mmol) in water (50 mL) and ammonia (3 mL) was added a suspension ofRaney Nickel in water (20 mL). The mixture was heated at reflux for 16h, then hot filtered through celite (10 g) and washed with water (3×25mL). The filtrate was evaporated and the resultant solid was azeotropedwith toluene (2×50 mL) to furnish a white solid (0.75 g, 97%).

A mixture of 5-methyl-3H-pyrimidin-4-one (0.60 g, 3.6 mmol) andphosphorous oxychloride (2.0 mL) was heated at 90° C. for 2.5 h. Themixture was evaporated to dryness under reduced pressure and theresultant solid was purified by sublimation under reduced pressure tofurnish the title compound as a white solid. This compound was unstableto air and was used immediately in the next step.

Intermediate 23: 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23

General procedure C (See Example 1) was followed using isonipecotamide(380 mg, 3.0 mmol), 3,4,5-trichloropyridine (600 mg, 3.3 mmol),triethylamine (0.84 mL, 6.0 mmol) and NMP (18 mL). The crude product waspurified by flash column chromatography on silica gel (CH₂Cl₂/EtOH,95:5-91:9) to furnish the title compound as a white solid (0.676 g,83%); LC-MS (ESI, 4 min) R_(t) 1.46 min, m/z 274 (100%, [M+H]⁺); m/z(ESI) C₁₁H₁₃N₃OCl₂ requires 273.0436, found [M+H]⁺ 273.0446.

Intermediate 24: 1-(3,5-dichloropyridin-4-yl)piperidine-4-carbothioamide24

To a solution of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23(40 mg, 0.15 mmol) in THF (2 mL) was added Lawesson's reagent (71 mg,0.18 mmol) and the mixture was heated at reflux for 2.5 h. After coolingto r.t. the mixture was poured into a saturated solution of sodiumhydrogen carbonate (20 mL) and extracted with EtOAc (2×20 mL). Thecombined organic extracts were washed with water (20 mL), brine (20 mL),dried (MgSO₄) and concentrated under reduced pressure. The crude productwas purified by flash column chromatography on silica gel (CH₂Cl₂, MeOH,99:1) to furnish the title compound as a white solid (21 mg, 40%), m/z(ESI) C₁₁H₁₄Cl₂N₂S requires 290.0280 found [M+H]⁺ 290.0280.

Example 1 1-(3,5-dichloropyridin-4-yl)-N-methylpiperidine-4-carboxamideE1

General Procedure C

To a solution of N-methylpiperidine-4-carboxamide 5 (26 mg, 0.18 mmol)and 3,4,5-trichloropyridine (33 mg, 0.18 mmol) in NMP (1.5 mL) was addedtriethylamine (76 μL, 0.54 mmol). The mixture was heated in a microwavereactor at 220° C. for 60 min, cooled to r.t. and then poured into asaturated solution of sodium hydrogen carbonate (50 mL). The solutionwas extracted with EtOAc (2×25 mL), the combined organic extracts werewashed with water (50 mL), brine (50 mL), dried (MgSO₄) and the solventwas removed under reduced pressure. The crude product was purified byflash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnishthe title compound as a white solid (46 mg, 88%), m.p. 175-177° C.;υ_(max) (CHCl₃)/cm⁻¹ 3462, 3006, 2853, 1665, 1558, 1385, 1146, 1096; m/z(ESI) C₁₂H₁₆Cl₂N₃O requires 288.0665, found [M+H]⁺ 288.0664.

Example 21-(3,5-dichloropyridin-4-yl)-N,N-dimethylpiperidine-4-carboxamide E2

General procedure C was followed usingN,N-dimethylpiperidine-4-carboxamide 6 (43 mg, 0.27 mmol),3,4,5-trichloropyridine (50 mg, 0.27 mmol), triethylamine (76 μL, 0.54mmol) and NMP (1.5 mL). The crude product was purified by flash columnchromatography on silica gel (hexane/EtOAc, 1:1) to furnish the titlecompound as a white solid (66 mg, 80%), m.p. 120-122° C.; υ_(max)(CHCl₃)/cm⁺ 3026, 2850, 1631, 1559, 1140, 1092, 934; m/z (ESI)C₁₃H₁₈Cl₂N₃O requires 302.0821, found [M+H]⁺ 302.0823.

Example 3 (1-(3,5-dichloropyridin-4-yl)piperidin-4-yl)(morpholino)methanone E3

General procedure C was followed usingmorpholino(piperidin-4-yl)methanone (21 mg, 0.12 mmol),3,4,5-trichloropyridine (23 mg, 0.12 mmol), triethylamine (32 μL, 0.23mmol) and NMP (1 mL). The crude product was purified by flash columnchromatography on silica gel (hexane/EtOAc, 1:1) to furnish the titlecompound as a white solid (15 mg, 35%), m.p. 172-174° C.; υ_(max)(CHCl₃)/cm⁻¹ 3006, 2858, 1632, 1559, 1448, 1116, 1020; m/z (ESI)C₁₅H₂₀Cl₂N₃O₂ requires 344.0927, found [M+H]⁺ 344.0929.

Example 41-(3-chloro-5-(3,4-dimethoxyphenyl)pyridin-4-yl)piperidine-4-carboxamideE4

General Procedure D

To a mixture of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23(24 mg, 0.088 mmol), 3,4-diimethoxyphenyllboronic acid (19 mg, 0.11mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %) inacetonitrile (1 mL) was added a 0.5 M aqueous solution of sodiumcarbonate (0.25 mL, 0.12 mmol). The mixture was heated at 150° C. in amicrowave reactor for 45 min, then cooled to r.t. and purified on anSCX-2 cartridge (MeOH followed by 0.5 M NH₃ in MeOH). The crude productwas purified by preparative tlc on silica gel (CH₂Cl₂, MeOH, 10:1) togive impure title compound (7 mg). Further purification by preparativehplc (H₂O, MeCN, 90:10-10:90, 30 min) furnished the title compound as awhite solid, LC-MS (ESI, 3.5 min) R_(t) 1.60 min, m/z 376 (100%,[M+H]⁺); m/z (ESI) C₁₉H₂₃ClN₃O₃ requires 376.1428 found [M+H]⁺ 376.1421.

Example 51-(3,5-dichloropyridin-4-yl)-N-(2-(3,5-dichloropyridin-4-ylamino)ethyl)piperidine-4-carboxamideE5

General procedure C was followed usingbenzyl-N-(amino-ethyl)piperidine-4-carboxamide 7 (47 mg, 0.27 mmol),3,4,5-trichloropyridine (50 mg, 0.27 mmol), triethylamine (76 μL, 0.54mmol) and NMP (1.5 mL). The crude product was purified by flash columnchromatography on silica gel (hexane/EtOAc, 1:1) to furnish the titlecompound as a white solid (81 mg, 64%), m.p. 157-159° C.; υ_(max)(CHCl₃)/cm⁻¹ 3013, 1670, 1574, 1510, 1231, 1092; m/z (ESI) C₁₈H₂₀Cl₄N₅Orequires 462.0417, found [M+H]⁺ 462.0421.

Example 6 4(3-methylpyridin-4-yl)cyclohexanecarboxamide E6

A solution of 4-chloro-3-methylpyridine hydrochloride (50 mg, 30 mmol)and isonipecotamide (0.12 g, 0.91 mmol) in water (1 mL) was heated at100° C. for 45 min in a microwave reactor. The reaction mixture wascooled to 0° C. and the mixture was filtered and washed with Et₂O (2×10mL) to furnish the title compound as a colourless, crystalline solid (33mg, 49%), m.p. 175-177° C.; m/z (ESI) C₁₂H₁₈CN₃O requires 220.1444,found [M+H]⁺ 220.1445.

Example 7 4-(4-carbamoylpiperidin-1-yl)-3,5-dichloropyridine 1-oxide E7

To a solution of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23(100 mg, 0.36 mmol) and hydrogen peroxide.urea complex (72 mg, 0.77mmol) in CH₂Cl₂ (2 mL) cooled to 0° C. was added trifluoroaceticanhydride (0.10 mL, 0.73 mmol). After 30 min the solution was warmed tor.t., after a further 16 hours a saturated solution of Na₂S₂O₅ (10 mL)was added. The mixture was extracted with CH₂Cl₂ (2×20 mL), the combinedorganic extracts were washed with a saturated solution of NaHCO₃ (20mL), brine (20 mL), dried (MgSO₄) and the solvent removed under reducedpressure. The crude product was purified by flash column chromatographyon silica gel (CH₂Cl₂/MeOH, 98:2) to furnish the title compound as awhite solid (20 mg, 19%), m.p. 130-133° C.; υ_(max) (CHCl₃)/cm⁻¹ 3026,2855, 1724, 1452, 1273, 1107.

Example 8 (4-(3,5-dichloropyridin-4-yl)piperazin-1-yl)(phenyl)methanoneE8

General procedure C was followed using 4-benzoylpiperazine 10 (47 mg,0.25 mmol), 3,4,5-trichloropyridine (72 mg, 0.39 mmol), triethylamine(0.11 mL, 0.78 mmol) and NMP (1.5 mL). The crude product was purified byflash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnishthe title compound as a white solid (19 mg, 23%), m.p. 132-134° C.;υ_(max) (CHCl₃)/cm⁻¹ 3005, 1627, 1435, 1286, 1153, 1010; m/z (ESI)C₁₆H₁₆Cl₂N₃O requires 336.0665, found [M+H]⁺ 336.0661.

Example 9 1-(4-(3,5-dichloropyridin-4-yl)piperazin-1-yl)ethanone E9

General procedure C was followed using acetylpiperazine (35 mg, 0.27mmol), 3,4,5-trichloropyridine (50 mg, 0.27 mmol), triethylamine (0.76μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flashcolumn chromatography on silica gel (hexane/EtOAc, 1:1) to furnish thetitle compound as a white solid (18 mg, 24%), m.p. 144-146° C.; υ_(max)(CHCl₃)/cm⁻¹ 3008, 2909, 2856, 1638, 1558, 1470, 1441, 1282, 1240, 1152,1098; m/z (ESI) C₁₁H₁₄Cl₂N₃O requires 274.0508, found [M+H]⁺ 274.0513.

Example 10 1-(3,5-dichloropyridin-4-yl)-4-methylpiperazine E10

General procedure C was followed using N-methylpiperazine (27 mg, 0.27mmol), 3,4,5-trichloropyridine (50 mg, 0.27 mmol), triethylamine (0.76μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flashcolumn chromatography on silica gel (hexane/EtOAc, 1:1) to furnish thetitle compound as a colourless oil (44 mg, 65%), υ_(max) (CHCl₃)/cm⁻¹2942, 2849, 2803, 1558, 1449, 1289, 1151; m/z (ESI) C₁₀H₇₄Cl₂N₃ requires246.0559, found [M+H]⁺ 246.0560.

Example 11 1-(3,5-dichloropyridin-4-yl)-4-ethylpiperazine E11

General procedure C was followed using N-ethylpiperazine (31 mg, 0.27mmol), 3,4,5-trichloropyridine (50 mg, 0.27 mmol), triethylamine (0.76μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flashcolumn chromatography on silica gel (hexane/EtOAc, 1:1) to furnish thetitle compound as a colourless oil (47 mg, 66%), υ_(max) (CHCl₃)/cm⁻¹2975, 2820, 1559, 1448, 1245, 1151, 957; m/z (ESI) C₁₁H₁₆Cl₂N₃ requires260.0716, found [M+H]⁺ 260.0719.

Example 12 1-(3-chloropyridin-4-yl)piperidine-4-carboxamide E12

General procedure C was followed using isonipecotamide (43 mg, 0.34mmol), 3,4,dichloropyridine (50 mg, 0.34 mmol), triethylamine (0.14 mL,1.0 mmol) and NMP (1.5 mL). The crude product was purified by flashcolumn chromatography on silica gel (hexane/EtOAc, 1:1) to furnish thetitle compound as a colourless oil (18 mg, 22%), m.p. 210-212° C.;υ_(max) (CHCl₃)/cm⁻¹ 2360, 2342, 1653, 1581, 1382, 1223, 1135, 1041; m/z(ESI) C₁₁H₁₃ClN₃O requires 240.0898, found [M+H]⁺ 240.0899.

Example 13N-(2-aminoethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamideE13

To a solution ofbenzyl-2-(1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamido)ethylcarbamate11 (0.45 g, 1.0 mmol) in acetonitrile and dichloromethane (1:1 mixture,40 mL), cooled to 0° C. was added trimethylsilyl iodide (0.57 mL, 4.0mmol). After stirring for 60 min, the solvent was removed under reducedpressure and the crude product was purified by flash columnchromatography on silica gel (CH₂Cl₂/MeOH, 98:2) to furnish the titlecompound as a colourless oil (193 mg, 61%), υ_(max) (CHCl₃)/cm⁻¹ 3002,2853, 1663, 1559, 1512, 1457, 1264, 1146; m/z (ESI) C₁₃H₁₉Cl₂N₄Orequires 317.0930, found [M+H]⁺ 317.0928.

Example 14N-(2-(benzylamino)ethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamideE14

To a solution ofN-(2-aminoethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamideE13 (50 mg, 0.16 mmol) in MeOH (5 mL) was added benzaldehyde (16 μL,0.16 mmol). After stirring for 2 h, sodium cyanoborohydride (20 mg, 0.32mmol) was added and the mixture was stirred for a further 20 h. Thesolvent was removed under reduced pressure, the residue was dissolved inEtOAc (20 mL), washed with a saturated solution of sodiumhydrogencarbonate (25 mL), brine (25 mL), dried (MgSO₄) and the solventwas removed under reduced pressure. The crude product was purified bypreparative tlc on silica gel (CH₂Cl₂, MeOH, 9:1) to furnish the titlecompound as a colourless oil (19 mg, 30%), υ_(max) (CHCl₃)/cm⁻¹ 3015,2850, 1659, 1558, 1512, 1236, 1146, 1036, 934; m/z (ESI) C₂₀H₂₅Cl₂N₄Orequires 407.1400, found [M+H]⁺ 407.1401.

Example 151-(3,5-dichloropyridin-4-yl)-N-(2-(4-methoxybenzylamino)ethyl)piperidine-4-carboxamideE15

To a solution ofN-(2-aminoethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamideE13 (50 mg, 0.16 mmol) in MeOH (5 mL) was added anisaldehyde (19 μL,0.16 mmol). After stirring for 2 h, sodium cyanoborohydride (20 mg, 0.32mmol) was added and the mixture was stirred for a further 20 h. Thesolvent was removed under reduced pressure, the residue was dissolved inEtOAc (20 mL), washed with a saturated solution of sodiumhydrogencarbonate (25 mL), brine (25 mL), dried (MgSO₄) and the solventwas removed under reduced pressure. The crude product was purified bypreparative tlc on silica gel (CH₂Cl₂, MeOH, 9:1) to furnish the titlecompound as a colourless oil (13 mg, 19%), υ_(max) (CHCl₃)/cm⁻¹ 3008,2839, 1660, 1513, 1249, 1174, 1036; m/z (ESI) C₂₁H₂₇Cl₂N₄O₂ requires437.1506, found [M+H]⁺ 437.1508.

Example 16N-(2-(cyclohexylmethylamino)ethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamideE16

To a solution ofN-(2-aminoethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamideE13 (50 mg, 0.16 mmol) in MeOH (5 mL) was added cyclohexanecarbaldehyde(19 μL, 0.16 mmol). After stirring for 2 h, sodium cyanoborohydride (20mg, 0.32 mmol) was added and the mixture was stirred for a further 16 h.The solvent was removed under reduced pressure, the residue wasdissolved in EtOAc (20 mL), washed with a saturated solution of sodiumhydrogencarbonate (25 mL), brine (25 mL), dried (MgSO₄) and the solventwas removed under reduced pressure. The crude product was purified bypreparative tlc on silica gel (CH₂Cl₂, MeOH, 9:1) to furnish the titlecompound as a white solid (15 mg, 23%), m.p. 174-177° C.; υ_(max)(CHCl₃)/cm⁺ 2932, 2856, 1665, 1558, 1457, 1236, 1146, 1037; m/z (ESI)C₂₀H₃₁Cl2₂N₄O requires 413.1869, found [M+H]⁺ 413.1875.

Example 17 N-(2-(dibenzylamino)ethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide E17

To a solution ofN-(2-aminoethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamideE13 (20 mg, 0.060 mmol) in MeOH (2 mL) was added benzaldehyde (19 μL,0.19 mmol). After stirring for 45 min, sodium cyanoborohydride (12 mg,0.19 mmol) was added and the mixture was stirred for a further 16 h. Thesolvent was removed under reduced pressure, the residue was dissolved inEtOAc (20 mL), washed with a saturated solution of sodiumhydrogencarbonate (25 mL), brine (25 mL), dried (MgSO₄) and the solventwas removed under reduced pressure. The crude product was purified bypreparative tlc on silica gel (CH₂Cl₂, MeOH, 9:1) to furnish the titlecompound as a white solid (14 mg, 54%), m.p. 147-149° C.; υ_(max)(CHCl₃)/cm⁻¹ 3007, 2837, 1658, 1558, 1509, 1457, 1146; m/z (ESI)C₂₇H₃₁Cl₂N₄O requires 497.1869, found [M+H]⁺ 497.1872.

Example 18N-(2-(bis(cyclohexylmethyl)amino)ethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamideE18

To a solution ofN-(2-aminoethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamideE13 (20 mg, 0.060 mmol) in MeOH (2 mL) was added cyclohexanecarbaldehyde(23 μL, 0.19 mmol). After stirring for 30 min, sodium cyanoborohydride(12 mg, 0.19 mmol) was added and the mixture was stirred for a further16 h. The solvent was removed under reduced pressure, the residue wasdissolved in EtOAc (20 mL), washed with a saturated solution of sodiumhydrogencarbonate (25 mL), brine (25 mL), dried (MgSO₄) and the solventwas removed under reduced pressure. The crude product was purified bypreparative tlc on silica gel (CH₂Cl₂, MeOH, 9:1) to furnish the titlecompound as a white solid (28 mg, 87%), m.p. 236-238° C.; υ_(max)(CHCl₃)/cm⁻¹ 2926, 2852, 1656, 1510, 1384, 1099; m/z (ESI) C₂₇H₄₂Cl₂N₄Orequires 509.2808, found [M+H]⁺ 509.2808.

Example 19N-(2-benzamidoethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamideE19

To a solution ofN-(2-aminoethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamideE13 (50 mg, 0.16 mmol), benzoic acid (23 mg, 0.19 mmol) and HATU (72 mg,0.19 mmol) in DMF (1 mL) was added DIPEA (82 μL, 0.47 mmol). After 16 hthe mixture was poured into a saturated solution of sodium hydrogencarbonate (50 mL) and extracted with EtOAc (2×25 mL). The combinedorganic extracts were washed with water (50 mL), a saturated solution ofcitric acid (50 mL) water (50 mL) and brine (50 mL), dried (MgSO₄) andconcentrated under reduced pressure. The crude product was purified bypreparative tlc on silica gel (CH₂Cl₂, MeOH, 9:1) to furnish the titlecompound as a white solid (24 mg, 36%), m.p. 209-211° C.; υ_(max)(CHCl₃)/cm⁻¹3029, 3006, 1656, 1523, 1385, 1228, 1017; m/z (ESI)C₂₀H₂₂Cl₂N₄NaO₂ requires 443.1012, found [M+Na]⁺ 443.1013.

Example 20(1-(3,5-dichloropyridin-4-yl)piperidin-4-yl)(piperazin-1-yl)methanoneE20

To a solution ofbenzyl-4-(1-(3,5-dichloropyridin-4-yl)piperidine-4-carbonyl)piperazine-1-carboxylate 13 (40 mg, 0.080 mmol) in DCM (1 mL), cooled to0° C. was added trimethylsilyliodide (24 μL, 0.16 mmol) and the solutionwas stirred at this temperature for 90 min, after which timetrimethylsilyl iodide (48 μL, 0.32 mmol) was added and the mixturewarmed to room temperature. After stirring for a further 45 min, thesolution was concentrated under reduced pressure and the crude productwas purified on an SCX-2 cartridge (MeOH followed by 0.5 M NH₃ in MeOH)to furnish the title compound as a yellow solid (27 mg, 94%), m.p.256-258° C.; m/z (ESI) C₁₅H₂₀Cl₂N₄NaO requires 365.0906, found [M+Na]⁺365.0909.

Example 21 1-(3,5-dichloropyridin-4-yl)pyrrolidine-3-carboxamide E21

A solution of 1-(3,5-dichloropyridin-4-yl)pyrrolidine-3-carbonitrile 14(83 mg, 0.34 mmol) in sulphuric acid (3 mL) was stirred for 90 min andthen poured onto ice/water (100 g). The mixture was made basic by theaddition of a 2 M solution of sodium hydroxide and extracted with EtOAc(2×50 mL). The combined organic extracts were washed with water (50 mL),brine (50 mL), dried (MgSO₄) and concentrated under reduced pressure, tofurnish the title compound as a white solid (65 mg, 73%), m.p. 161-163°C.; υ_(max) (CHCl₃)/cm⁻¹3053, 2985, 1689, 1558, 1465; m/z (ESI)C₁₀H₁₂Cl₂N₃O requires 260.0352 found [M+H]⁺ 260.0355.

Example 22 1-(3,5-dibromopyridine-4-yl)pyrrolidine-3-carboxamide E22 andExample 23 1-(3,5-dibromopyridine-4-yl)pyrrolidine-3-carbonitrile E23

General procedure C was followed using 3,5-dibromo-4-chloropyridine (71mg, 0.26 mmol), 3-cyanopyrrolidine (25 mg, 0.26 mmol), NMP (3 mL) andtriethylamine (72 μL, 0.52 mmol). The crude product was purified byflash column chromatography on silica gel (CH₂Cl₂, MeOH, 99:1) tofurnish the title compound E22 as a white solid (9 mg, 10%), m.p.159-161° C.; υ_(max) (CHCl₃)/cm⁻¹ 3022, 3008, 1678, 1591, 1446, 1235;m/z (ESI) C₁₀H₁₂Br₂N₃O requires 347.9342, found [M+H]⁺ 347.9339.

Also isolated from the purification procedure was1-(3,5-dibromopyridin-4-yl)pyrrolidine-3-carbonitrile E23 as acolourless oil (13 mg, 15%), υ_(max) (CHCl₃)/cm⁻¹ 3014, 2988, 2246,1731m 1451m 1374, 1248, 1045, 1016; m/z (ESI) C₁₀H₁₀Br₂N₃ requires329.9236, found [M+H]⁺ 329.9238.

Example 24 (R,S)-1-(3,5-dichloro-pyridin-4-yl)-pyrrolidine-3-carboxylicacid (2-amino-ethyl)-amide E24

To a solution of(R,S)-(2-{[1-(3,5-dichloro-pyridin-4-yl)-pyrrolidine-3-carbonyl]-amino}-ethyl)-carbamicacid benzyl ester 17 (50 mg, 0.11 mmol) in dichloromethane (2 mL),cooled to 0° C., was added iodotrimethylsilane (66 μL, 0.46 mmol). Afterstirring at this temperature for 2 h, the solvent was removed underreduced pressure and the crude product was purified on an SCX-2cartridge (MeOH followed by 0.5 M NH₃ in MeOH) to furnish the titlecompound as a colourless oil (16 mg, 46%), υ_(max) (CHCl₃)/cm⁻¹ 3014,1731, 1664, 1559, 1519, 1465, 1248, 1046; m/z (ESI) C₁₂H₁₆Cl₂N₄NaOrequires 325.0593, found [M+Na]⁺ 325.0595.

Example 25 1-(3,5-dibromo-pyridin-4-yl)-pyrrolidine-3-carboxylic acid(2-amino-ethyl)-amide E25

To a solution ofbenzyl-2-(1-(3,5-dibromopyridin-4-yl)pyrrolidine-3-carboxamido)ethylcarbamate19 (65 mg, 0.12 mmol) in dichloromethane (2 mL), cooled to 0° C., wasadded iodotrimethylsilane (70 μL, 0.49 mmol). After stirring at thistemperature for 2 h, the solvent was removed under reduced pressure andthe crude product was purified on an SCX-2 cartridge (MeOH followed by0.5 M NH₃ in MeOH) to furnish the title compound as a colourless oil (40mg, 83%), υ_(max) (CHCl₃)/cm⁻¹ 3022, 2871, 1664, 1556, 1450, 1399; m/z(ESI) C₁₂H₁₆Br₂N₄NaO requires 412.9583, found [M+H]⁺ 412.9582.

Example 26 4-(3,5-dimethylpyridin-4-yl)cyclohexanecarboxamide E26

A solution of 4-chloro-3,5-dimethylpyridine hydrochloride (0.10 g, 0.56mmol) and isonipecotamide (0.22 mg, 1.7 mmol) in water (1.5 mL) washeated at 175° C. for 60 min, in a microwave reactor. The mixture waspoured into a saturated solution of sodium hydrogen carbonate (20 mL),extracted with EtOAc (2×20 mL). The combined organic extracts were dried(MgSO₄) and concentrated under reduced pressure. The crude product waspurified by flash column chromatography on silica gel (CH₂Cl₂, MeOH,95:5) to furnish the title compound as a white solid (5 mg, 4%), m/z 234(100%, [M+H]⁺); m/z (ESI) C₁₃H₂₀N₃O requires 234.1601 found [M+H]⁺234.1600.

Example 27 1-(3,5-dibromopyridin-4-yl)piperidine-4-carboxamide E27

General procedure C was followed using 3,5-dibromo-4-chloropyridine 18(50 mg, 0.18 mmol), isonipecotamide (24 mg, 0.18 mmol), NMP (2 mL) andtriethylamine (51 μL, 0.37 mmol). The crude product was purified bypreparative tlc on silica gel (CH₂Cl₂, MeOH, 9:1) to furnish the titlecompound as a pale yellow solid (29 mg, 43%), m.p. 158-160° C.; υ_(max)(CHCl₃)/cm⁻¹ 3053, 2985, 1687, 1591; m/z (ESI) C₁₁H₁₄Br₂N₃O requires361.9498 found [M+H]⁺ 361.9500.

Example 28 1-(5-chloropyrimidin-4-yl)piperidine-4-carboxamide E28

To a solution of 4,5-dichloropyrimidine hydrochloride 20 (0.20 g, 1.1mmol) in DMF (4 mL) was added triethylamine (1.5 mL, 10 mmol). Afterstirring for 30 min, a solution of isonipecotamide (0.42 mg, 3.3 mmol)in DMF (4 mL) was added and the mixture was stirred at r.t. for afurther 16 h. The mixture was poured into a saturated solution of sodiumhydrogen carbonate (50 mL) and extracted with EtOAc (2×25 mL). Thecombined organic extracts were washed with water (25 mL), brine (25 mL),dried (MgSO₄) and concentrated under reduced pressure. The crude productwas purified by flash column chromatography on silica gel (CH₂Cl₂, MeOH,gradient 98:2-96:4) to furnish the title compound as a white solid (51mg, 20%), m.p. 201-202° C.; u (CHCl₃)/cm⁻¹ 3023, 3014, 1724, 1682, 1448,1360, 1219, 1037; m/z (ESI) C₁₀H₁₄CN₄O requires 241.0851, found [M+H]⁺241.0851.

Example 29 1-(5-bromopyrimidin-4-yl)piperidine-4-carboxamide E29

To a solution of 5-bromo-4-chloropyrimidine hydrochloride 21 (0.10 g,0.36 mmol) in DMF (2 mL) was added triethylamine (0.51 mL, 3.6 mmol).After stirring for 30 min, a solution of isonipecotamide (0.14 g, 1.1mmol) in DMF (2 mL) was added and the mixture was stirred at r.t. for afurther 16 h. The mixture was poured into a saturated solution of sodiumhydrogen carbonate (50 mL) and extracted with EtOAc (2×25 mL). Thecombined organic extracts were washed with water (25 mL), brine (25 mL),dried (MgSO₄) and concentrated under reduced pressure. The crude productwas purified by flash column chromatography on silica gel (CH₂Cl₂, MeOH,98:2) to furnish the title compound as a white solid (60 mg, 58%), m.p.188-190° C.; υ_(max) (CHCl₃)/cm⁻¹ 3012, 2853, 1682, 1566, 1447, 1359,1144, 1017, 950; m/z (ESI) C₁₀H₁₄BrN₄O requires 285.0346, found [M+H]⁺285.0344.

Example 30 1-(5-methylpyrimidin-4-yl)piperidine-4-carboxamide E30

To a solution of 5-methyl-4-chloropyrimidine hydrochloride 22 (75 mg,0.45 mmol) in DMF (2 mL) was added triethylamine (0.63 mL, 4.5 mmol).After stirring for 15 min, a solution of isonipecotamide (64 mg, 0.50mmol) in DMF (2 mL) was added and the mixture was stirred at r.t. for afurther 20 h. The mixture was poured into a saturated solution of sodiumhydrogen carbonate (50 mL) and extracted with EtOAc (2×25 mL). Thecombined organic extracts were washed with water (25 mL), brine (25 mL),dried (MgSO₄) and concentrated under reduced pressure. The crude productwas purified by flash column chromatography on silica gel (CH₂Cl₂, MeOH,gradient 98:2 to 9:1) to furnish the title compound as a white solid (25mg, 25%), m.p. 182-184° C.; υ_(max) (CHCl₃)/cm⁻¹ 3024, 1678, 1581, 1439,1359, 1147, 948; m/z (ESI) C₁₁H₁₂R₄O requires 221.1397, found [M+H]⁺221.1394.

Example 31 1-(5-bromo-2-chloropyrimidin-4-yl)piperidine-4-carboxamideE31

To a solution of 5-bromo-2,4-dichloropyrimidine (0.11 g, 0.50 mmol) andisonipecotamide (77 mg, 0.60 mmol) in DMF (2 mL) was added triethylamine(77 μL, 0.55 mmol) and the mixture was stirred at r.t. for 4.5 h. Themixture was poured into a saturated solution of sodium hydrogencarbonate (10 mL) and extracted with EtOAc (2×10 mL). The combinedorganic extracts were washed with water (10 mL), brine (10 mL), dried(MgSO₄) and concentrated under reduced pressure. The crude product waspurified by flash column chromatography on silica gel (CH₂Cl₂, MeOH,98:2) to furnish the title compound as a white solid (174 mg, 95%), m/z(ESI) C₁₀H₁₂BrClN₄NaO requires 340.9775 found [M+Na]⁺ 340.9776.

Example 32 1-(2-chloro-5-phenylpyrimidin-4-yl)piperidine-4-carboxamideE32

To a solution of1-(5-bromo-2-chloropyrimidin-4-yl)piperidine-4-carboxamide E31 (0.10 g,0.31 mmol), benzene boronic acid (46 mg, 0.38 mmol) andtetrakis(triphenylphosphine)palladium(0) (20 mg, 5 mol %) in DME (8 mL)was added a 0.5 M solution of sodium carbonate. The mixture was heatedat reflux for 22 h, then cooled to r.t. and purified on an SCX-2cartridge (MeOH, followed by 0.5 M NH₃ in MeOH). The crude product waspurified by chromatography on silica gel (CH₂Cl₂, MeOH, 98:2) to furnishthe title compound as a white solid (58 mg, 59%), m/z 317 (100%, MK);m/z (ESI) C₁₆H₁₈BrClN₄O requires 317.1165 found [M+H]⁺ 317.1161.

Example 33 1-(5-phenylpyrimidin-4-yl)piperidine-4-carboxamide E33

A mixture of 1-(2-chloro-5-phenylpyrimidin-4-yl)piperidine-4-carboxamideE32 (35 mg, 0.11 mmol), potassium acetate (22 mg, 0.22 mmol) and 10% wtpalladium on carbon (3.5 mg) in acetic acid (2 mL) was stirred under anatmosphere of hydrogen (1 atm) for 18 h. The mixture was filteredthrough celite, washed with AcOH (2×10 mL) and concentrated underreduced pressure. The crude product was purified by preparative tlc onsilica gel (CH₂Cl₂/MeOH, 10:1) to furnish the title compound as a whitesolid (9 mg, 29%) m/z 283 (100%, [M+H]⁺); m/z (ESI) C₁₆H₁₉N₄O requires283.1553 found [M+H]⁺ 283.1549.

Example 35 2-(1-(3,5-dichloropyridin-4-yl)piperidin-4-yl)thiazole E34

To a solution of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carbothioamide24 (23 mg, 0.079 mmol) in ethanol (2 mL) was added chloroacetaldehyde(50% wt in H₂O) (0.26 mL, 0.16 mmol) and the mixture was heated atreflux for 17 h. The mixture was concentrated and chloroform (10 mL) wasadded to the residue. The solution was washed with water (10 mL) andextracted with chloroform (10 mL). The combined organic extracts werewashed with brine (10 mL), dried (MgSO₄) and concentrated under reducedpressure to furnish a brown oil (40 mg). The crude product was purifiedby preparative tlc on silica gel (CH₂Cl₂, MeOH, 10:1, then hexane,EtOAc, 1:1) to furnish the title compound as a pale brown solid (5 mg,20%), LC-MS (ESI) R_(t) 2.79 min, m/z 314 (100%, M⁺).

Example 35 2-(1-(3,5-dichloropyridin-4-yl)piperidin-4-yl)oxazole E35

To a solution of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23(0.10 g, 0.36 mmol) in polyphosphoric acid (5 mL) at 80° C. was addedvinylene carbonate (35 mg, 0.40 mmol). The mixture was heated at 170° C.for 4 hours, cooled to r.t. and poured into water (200 mL). The mixturewas extracted with ethyl acetate (3×50 mL) and the combined organicextracts were washed with water (100 mL), a saturated solution of sodiumhydrogen carbonate (50 mL), water (50 mL), brine (50 mL), dried (MgSO₄)and concentrated under reduced pressure to furnish a colourless oil (12mg). The crude product was purified by preparative tlc on silica gel(CH₂Cl₂, MeOH, 10:1 then hexane, EtOAc, 1:1) to furnish the titlecompound as a white solid (13 mg, 12%), LC-MS (ESI) R_(t) 2.66 min, m/z298 (100%, M⁺); m/z (ESI) C₁₃H₁₄Cl₂N₃O requires 298.0508 found [M+H]⁺298.0507.

Example 36 1(3-bromopyridin-4-yl)piperidine-4-carboxamide E36

General procedure C was followed using 3-bromo-4-chloro-pyridine (0.10g, 0.52 mmol) and isonipecotamide (67 mg, 0.52 mmol) NMP (2 mL) andtriethylamine (0.14 mL, 1.0 mmol). The crude product was purified byflash column chromatography on silica gel (CH₂Cl₂, MeOH, gradient 99:1to 95:5) to furnish the title compound as a white solid (49 mg, 33%),LC-MS (ESI) R_(t) 0.80 min, m/z 284 (100%, [M+H]⁺); m/z (ESI)C₁₁H₁₅BrN₃O requires 284.0393 found [M+H]⁺ 284.0392.

Example 37 1-(3-(4-methoxyphenyl)pyridin-4-yl)piperidine-4-carboxamideE37

General procedure D (See Example 4) was followed using1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (50 mg, 0.17 mmol),4-methoxyphenylboronic acid (32 mg, 0.21 mmol),tetrakis(triphenylphosphine)palladium(0) (10 mg, 5 mol %), acetonitrile(1.2 mL) and 0.5 M sodium carbonate (0.49 mL, 0.25 mmol) for 50 min. Thecrude product was purified by flash column chromatography on silica gel(CH₂Cl₂, MeOH, gradient 97:3 to 95:5) to furnish the title compound as awhite solid (49 mg, 89%), LC-MS (ESI) R_(t) 1.28 min, m/z 312 (100%,[M+H]⁺); m/z (ESI) C₁₈H₂₂N₃O₂ requires 312.1706 found [M+H]⁺ 312.1705.

Example 38 1-(3-(thiophen-2-yl)pyridin-4-yl)piperidine-4-carboxamide E38

General procedure D (See Example 4) was followed using1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (25 mg, 0.088 mmol),thiophene-2-boronic acid (13 mg, 0.11 mmol),tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile(1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. Thecrude product was purified by preparative tlc on silica gel (CH₂Cl₂,MeOH, 10:1) to furnish the title compound as a white solid (23 mg, 91%),LC-MS (ESI)R, 1.17 min, m/z 288 (100%, [M+H]⁺); m/z (ESI) C₁₅H₁₈N₃OSrequires 288.1165 found [M+H]⁺ 288.1163.

Examples 39 and 401-(3-bromo-5-phenylpyridin-4-yl)piperidine-4-carboxamide E39 and1-(3,5-diphenylpyridin-4-yl)piperidine-4-carboxamide E40

To a solution of 1-(3,5-dibromopyridin-4-yl)piperidine-4-carboxamide E27(50 mg, 0.14 mmol), benzene boronic acid (70 mg, 0.58 mmol) andpotassium phosphate (0.20 g, 0.96 mmol) in toluene (1.5 mL) was addedtetrakis(triphenylphosphine)palladium(0) (18 mg, 0.014 mmol). Themixture was heated at 170° C. in a microwave reactor for 45 min, thenpoured into a saturated solution of sodium hydrogen carbonate (25 mL).The mixture was extracted with EtOAc (2×25 mL) and the combined organicextracts were washed with water (25 mL), brine (25 mL), dried (MgSO₄)and the solvent was removed under reduced pressure. The crude productwas purified by flash column chromatography on silica gel (CH₂Cl₂, MeOH,98:2) to furnish a 2:3 mixture of mono- and bis-coupled products.Analytical samples were further purified by preparative HPLC (MeCN, H₂O5:95):

1-(3-bromo-5-phenylpyridin-4-yl)piperidine-4-carboxamide E39

(4.2 mg, 8%), m.p. 220-222° C.; υ_(max) (CHCl₃)/cm⁻¹ 3029, 1684, 1441,1383; m/z (ESI) C₁₇H₁₉BrN₃O requires 360.0706, found [M+H]⁺ 360.0706.

1-(3,5-diphenylpyridin-4-yl)piperidine-4-carboxamide E40

(14 mg, 28%), υ_(max) (CHCl₃)/cm⁻¹ 3039, 1731, 1375, 1249, 1045, 1016;m/z (ESI) C₂₃H₂₄N₃O requires 358.1914, found [M+H]⁺ 358.1911.

Example 411-(3-bromo-5-(4-(trifluoromethylphenyl)pyridin-4-yl)piperidine-4-carboxamideE41

To a solution of 1-(3,5-dibromopyridin-4-yl)piperidine-4-carboxamide E27(50 mg, 0.14 mmol), 4-trifluoromethylbenzene boronic acid (0.11 g, 0.56mmol) and potassium phosphate (0.20 g, 0.96 mmol) in toluene (4 mL) wasadded tetrakis(triphenylphosphine)palladium(0) (18 mg, 10 mol %). Themixture was heated at 170° C. in a microwave reactor for 60 min, thenpoured into a saturated solution of sodium hydrogencarbonate (25 mL).The mixture was extracted with EtOAc (2×20 mL) and the combined organicextracts were washed with water (25 mL), brine (25 mL), dried (MgSO₄)and the solvent was removed under reduced pressure. The crude productwas purified by flash column chromatography on silica gel (CH₂Cl₂, MeOH,98:2) and further purified preparative hplc (H₂O, MeCN, gradient 90:10to 10:90 over 30 min) (11 mg, 9%), m/z (ESI) C₁₈H₁₈BrF₃N₃O requires428.0580 found [M+F]⁺ 428.0574.

Example 42 1-(3-chloro-5-phenylpyridin-4-yl)piperidine-4-carboxamide E42

General procedure D (See Example 4) was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088mmol), benzene boronic acid (13 mg, 0.11 mmol),tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile(1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. Thecrude product was purified by preparative hplc (H₂O, MeCN, gradient90:10 to 10:90 over 30 min) to furnish the title compound as a whitesolid (6 mg, 22%), LC-MS (ESI)R_(f) 1.63 min, m/z 316 (100%, [M+H]⁺);m/z (ESI) C₁₇H₁₈ClN₃NaO requires 338.1031 found [M+N]⁺ 338.1030.

Example 431-(3-chloro-5-(4-methoxyphenyl)pyridin-4-yl)piperidine-4-carboxamide E43

General procedure D (See Example 4) was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (24 mg, 0.088mmol), 4-methoxybenzene boronic acid (16 mg, 0.11 mmol),tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile(1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. Thecrude product was purified by preparative hplc (CH₃CN, H₂O, 23:77) tofurnish the title compound as a white solid (9 mg, 30%), LC-MS (ESI)R,1.67 min, m/z 346 (100%, [M+H]⁺); m/z (ESI) C₁₈H₂₁ClN₃O₂ requires346.1317 found [M+H]⁺ 346.1317.

Example 441-(3-chloro-5-(1H-pyrazol-5-yl)pyridin-4-yl)piperidine-4-carboxamide E44

General procedure D (See Example 4) was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (24 mg, 0.088mmol), 1H-pyrazole-5-boronic acid pinacol ester (19 mg, 0.11 mmol),tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile(1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. Thecrude product was purified by preparative tlc on silica gel (CH₂Cl₂,MeOH, 10:1) to furnish the title compound as a white solid (18 mg, 67%),LC-MS (ESI) R_(t) 1.06 min, m/z 306 (100%, [M+H]⁺; m/z (ESI) C₁₄H₁₇ClN₅Orequires 306.1116 found [M+H]⁺ 306.1114.

Example 451-(3-chloro-5-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-4-yl)piperidine-4-carboxamideE45

General Procedure E

To a suspension of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide23 (75 mg, 0.27 mmol), 1,5-dimethyl-4-pyrazole boronic acid pinacolester (76 mg, 0.34 mmol) and tetrakis(triphenylphosphine)palladium(0)(16 mg, 5 mol %) in acetonitrile (3 mL) was added 0.5 M solution ofsodium carbonate (0.77 mL, 0.38 mmol). The mixture was heated to in amicrowave reactor at 150° C. for 45 min. Once cooled the reaction wasconcentrated in vacuo and dry loaded onto silica. The crude product waspurified by flash column chromatography on silica gel (CH₂Cl₂, EtOH,97:3-80:20, biotage 25+S) to furnish the title compound as a clearcolourless oil (24 mg, 26%), LC-MS (ESI, 4 min)R, 1.49 min, m/z 334(100%, [M+H]⁺); m/z (ESI) C₁₆H₂₀N₅OCl requires 333.1356, found [M+H]⁺333.1354.

Example 461-(3-chloro-5-(2-(methylthio)pyrimidin-5-yl)pyridin-4-yl)piperidine-4-carboxamideE46

General procedure E was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (75 mg, 0.27 mmol),2-(methylthio)pyrimidine-5-boronic acid (58 mg, 0.34 mmol),tetrakis(triphenylphosphine)palladium(0) (16 mg, 5 mol %), acetonitrile(3 mL) and 0.5 M sodium carbonate (0.77 mL, 0.38 mmol). The crudeproduct was purified by flash column chromatography on silica gel(CH₂Cl₂, EtOH, 96:4-82:18, biotage 25+S) to furnish the title compoundas an off white solid (11 mg, 11%), along with recovered1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide as a white solid(41 mg, 55% RSM), LC-MS (ESI, 4 min) R_(t) 2.14 min, m/z 364 (100%,[M+H]⁺); m/z (ESI) C₁₆H₁₈N₅OSCl requires 363.09206, found [M+H]⁺363.0922.

Example 471-(3-chloro-5-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-4-yl)piperidine-4-carboxamideE47

General procedure E was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (75 mg, 0.27 mmol),1,3-dimethyl-4-pinacolboranyl-1H-pyrazole (76 mg, 0.34 mmol),tetrakis(triphenylphosphine)palladium(0) (16 mg, 5 mol %), acetonitrile(3 mL) and 0.5 M sodium carbonate (0.77 mL, 0.38 mmol). The crudeproduct was purified by flash column chromatography on silica gel(CH₂Cl₂, EtOH, 94:6-80:20, biotage 25+S) to furnish the title compoundas a white solid (16 mg, 18%), along with recovered1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (30 mg, 40% RSM),LC-MS (ESI, 4 min) R_(t) 1.40 min, m/z 334 (100%, [M+H]⁺); m/z (ESI)C₁₆H₂₀N₅OCl requires 333.1356, found [M+H]⁺ 333.1356.

Example 48 1-(3,5-dichloropyridin-4-yl)piperidine-4-carbonitrile E48

General procedure C was followed using 3,4,5-trichloropyridine (0.50 g,2.7 mmol), isonipecotamide (0.30 mg, 2.7 mmol), NMP (15 mL) andtriethylamine (0.76 mL, 5.5 mmol). The crude product was purified byflash column chromatography on silica gel (CH₂Cl₂, MeOH, 99:1) tofurnish the title compound as a white solid (228 mg, 33%), m/z (ESI)C₁₁H₁₂Cl₂N₃ requires 256.0403 found [M+H]⁺ 256.0409.

Example 491-(3,5-dichloropyridin-4-yl)-4-methylpiperidine-4-carbonitrile E49

To a solution of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carbonitrileE48 (90 mg, 0.35 mmol) in THF (1.5 mL), at −78° C., was added a 1Msolution of LDA in THF (0.38 mL, 0.38 mmol). The mixture was stirred for30 min at −78° C. before warming to r.t. After 60 min, methyl iodide (31μL, 0.5 mmol) was added. The mixture was stirred for a further 60 min atr.t. for 1 h, before addition of water (5 mL). The mixture was extractedwith CH₂Cl₂ (3×5 mL) and the combined organic extracts were dried overMgSO₄ and concentrated under reduced pressure to dryness. The crudeproduct was purified by flash column chromatography on silica gel(hexane, EtOAc, 100:0-80:20, biotage 25+M) to furnish the title compoundas a white solid (34 mg, 36%), along with recovered1-(3,5-dichloropyridin-4-yl)piperidine-4-carbonitrile (23 mg, 25%),LC-MS (ESI, 4 min)R, 3.09 min, m/z 270 (100%, M+); m/z (ESI) C₁₂H₁₃Cl₂N₃requires 269.0487 found [M+H]⁺ 289.0488.

Example 501-(3-chloro-5-(4-fluorophenyl)pyridin-4-yl)piperidine-4-carboxamide E50

General procedure D was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (24 mg, 0.088mmol), 4-fluorobenzene boronic acid (15 mg, 0.11 mmol) andtetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile(1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. Thecrude product was purified by preparative tlc on silica gel (CH₂Cl₂,MeOH, 10:1) to give impure title compound (19 mg) which was furtherpurified by preparative hplc (CH₃CN, H₂O, gradient 1:9 to 9:1) tofurnish the title compound as a white solid, LC-MS (ESI, 3.5 min)R, 1.71min, m/z 334 (100%, [M+H]⁺); m/z (ESI) C₁₇H₁₈ClFN₃O requires 334.1117found [M+H]⁺ 334.1116.

Example 511-(3-chloro-5-(4-trifluoromethyl)phenyl)pyridin-4-yl)piperidine-4-carboxamideE51

General procedure D was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (24 mg, 0.088mmol), (4-trifluoromethyl)benzene boronic acid (20 mg, 0.11 mmol) andtetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile(1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. Thecrude product was purified by preparative tlc on silica gel (CH₂Cl₂,MeOH, 10:1) followed by preparative hplc (CH₃CN, H₂O, gradient 1:9 to9:1) to furnish the title compound as a white solid (10 mg, 30%), LC-MS(ESI, 3.5 min)R, 2.26 min, m/z 384 (100%, [M+H]⁺); m/z (ESI)C₁₈H₁₈ClF₃N₃O requires 384.1085 found [M+1-1]⁺ 384.1084.

Example 521-(3-(4-fluoro-3-methylphenyl)pyridin-4-yl)piperidine-4-carboxamide E52

General procedure D was followed using1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (25 mg, 0.088 mmol),4-flouro-3-methylphenylboronic acid (16 mg, 0.11 mmol),tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), 0.5 M sodiumcarbonate (0.25 mL, 0.12 mmol) and acetonitrile (1 mL) for 50 min. Thecrude product was purified by preparative tlc (CH₂Cl₂, MeOH, 10:1) tofurnish the title compound as a white solid (15 mg, 56%), LC-MS (ESI 3.5min) R_(t) 1.46 min, m/z 314 (100%, [M+H]⁺); m/z (ESI) C₁₈H₂₁FN₃Orequires 314.1663 found [M+H]⁺ 314.1658.

Example 531-(3-(3,5-dimethylisoxazol-4-yl)pyridin-4-yl)piperidine-4-carboxamideE53

General procedure E was followed using1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (100 mg, 0.35 mmol),3,5-dimethyl-4-isoxazole boronic acid (74 mg, 0.53 mmol),tetrakis(triphenylphosphine)palladium(0) (20 mg, 5 mol %), acetonitrile(4 mL) and 0.5 M sodium carbonate (1.1 mL, 0.53 mmol). The crude productwas purified by flash column chromatography on silica gel (CH₂Cl₂, EtOH,97:3-80:20, biotage 25+S) to furnish the title compound as a white solid(18 mg, 17%), along with 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide(10 mg, 10% RSM), LC-MS (ESI, 4 min)R, 0.76 min, m/z 301 (100%, [M+H]⁺);m/z (ESI, R_(t) 1.22 min) C₁₆H₂₀N₄O₂ requires 300.1587, found[M+H]⁺300.1591.

Examples 54 and 558-(3,5-dichloropyridin-4-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-oneE54 and1-(3,5-dichloropyridin-4-yl)-4-(phenylamino)piperidine-4-carboxamide E55

General procedure D was followed using 3,4,5-trichloropyridine (120 mg,0.66 mmol), 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (150 mg, 0.66mmol), NMP (3.6 ml) and triethylamine (0.19 ml, 1.3 mmol) to give acrude orange/white oily solid (105 mg). The crude product was purifiedby flash column chromatography on silica gel (hexane, EtOAc,80:20-10:90, biotage 25+S) to furnish impure title compound E54 as anoff white solid (39 mg) and impure title compound E55 as an off whitesolid (97 mg). Both products where further purified by recrystallisationin EtOAc/Et₂O to furnish title compound E54 as an off white solid (13mg, 5%) and title compound E55 as an off white solid (46 mg, 19%).

8-(3,5-dichloropyridin-4-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-oneE54

LC-MS (ESI, 4 min)R_(t) 3.26 min, m/z 377 (100%, [M+H]⁺); m/z (ESI)C₁₈H₁₈N₄Cl₂O requires 376.0858, found [M+H]⁺ 364.0869.

1-(3,5-dichloropyridin-4-yl)-4-(phenylamino)piperidine-4-carboxamide E55

LC-MS (ESI, 4 min) R_(t) 2.99 min, m/z 365 (100%, [M+H]⁺); m/z (ESI)C₁₇H₁₈N₄Cl₂O requires 364.0858, found [M+H]⁺ 364.0851.

Example 561-(3-chloro-5-(pyrimidin-5-yl)pyridin-4-yl)piperidine-4carboxamide E56

General procedure D was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088mmol), pyrimidin-5-yl boronic acid (12 mg, 0.11 mmol) andtetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile(1 mL) and a 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. Thecrude product was purified by preparative tlc on silica gel (CH₂Cl₂,MeOH, 10:1) to furnish the title compound as a white solid (26 mg, 95%),LC-MS (ESI, 3.5 min) R_(t) 1.19 min, m/z 318 (100%, [M+H]⁺); m/z (ESI)C₁₅H₁₇ClN₅O requires 318.1116 found [M+H]⁺ 318.1114.

Example 57 1-(3-(thiophen-3-yl)pyridin-4-yl)piperidine-4-carboxamide E57

General procedure D was followed using1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (17 mg, 0.060 mmol),thiophene-3-boronic acid (9.2 mg, 0.072 mmol),tetrakis(triphenylphosphine)palladium(0) (3.5 mg, 5 mol %), 0.5 M sodiumcarbonate (0.17 mL, 0.084 mmol) and acetonitrile (1 mL) for 50 min. Thecrude product was purified by preparative tlc (CH₂Cl₂, MeOH, 10:1) tofurnish the title compound as a white solid (13 mg, 76%), LC-MS (ESI,3.5 min) R₁ 1.12 min, m/z 288 (100%, [M+H]⁺); m/z (ESI) C₁₅H₁₈N₃OSrequires 288.1165 found [M+H]⁺ 288.1163.

Example 581-(3-chloro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-4-yl)piperidine-4-carboxamideE58

General procedure E was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (75 mg, 0.27mmol), 1,3,5-trimethyl-1H-pyrazole-4-boronic pinacol ester (65 mg, 0.27mmol), tetrakis(triphenylphosphine)palladium(0) (16 mg, 5 mol %),acetonitrile (3 mL) and 0.5 M sodium carbonate (0.77 mL, 0.38 mmol). Thecrude product was purified by flash column chromatography on silica gel(CH₂Cl₂, EtOH, 94:6-80:20, biotage 25+S) to furnish the title compoundas a very pale yellow solid (34 mg, 35%), along with recovered1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (52 mg, 57% RSM),LC-MS (ESI, 4 min)R_(t) 1.55 min, m/z 348 (100%, [M+H]⁺); m/z (ESI)C₁₇H₂₂N₅OCl requires 347.1513, found [M+H]⁺ 347.1508.

Example 59 8-(3,5-dichloropyridin-4-yl)-2,8-diazaspiro[4.5]decan-1-oneE59

General procedure C was followed using 3,4,5-trichloropyridine (100 mg,0.55 mmol), 2,8-diazaspiro[4,5]decan-1-one.HCl (85 mg, 0.55 mmol,commercial ASW MedChem Inc.), NMP (3.0 ml) and triethylamine (0.23 ml,1.6 mmol) to give a crude orange/white oily solid (458 mg). The crudeproduct was purified by flash column chromatography on silica gel(CH₂Cl₂, MeOH, 97:3) to furnish impure title compound as an oily whitesolid (110 mg). Further purification by trituration in Et₂O furnishedthe title compound as a white solid (57 mg, 35%), LC-MS (ESI, 4 min)R_(t) 2.66 min, m/z 300 (100%, [M+H]⁺); m/z (ESI) C₁₃H₁₅N₃Cl₂0 requires299.0593, found [M+H]⁺ 300.0665.

Example 608-(3-chloro-5-phenylpyridin-4-yl)-2,8-diazaspiro[4.5]decan-1-one E60

General procedure E was followed using8-(3,5-dichloropyridin-4-yl)-2,8-diazaspiro[4.5]decan-1-one E59 (38 mg,0.13 mmol), phenyl boronic acid (19 mg, 0.16 mmol),tetrakis(triphenylphosphine)palladium(0) (7.3 mg, 5 mol %), acetonitrile(1.4 ml) and 0.5 M sodium carbonate (0.35 ml, 0.18 mmol). The crudeproduct was purified by flash column chromatography on silica gel(CH₂Cl₂, MeOH, 97:3) followed by preparative hplc (CH₃CN, H₂O, gradient1:9 to 9:1) to furnish the title compound as a white solid (12 mg, 28%),along with recovered starting material as a clear colourless oil (10 mg,23% RSM), LC-MS (ESI, 4 min) R_(t) 2.22 min, m/z 342 (100%, [M+H]⁺); m/z(ESI) C₁₉H₂₀N₃ClO requires 341.1295, found [M+H]⁺ 341.1301.

Example 61 (1-(3,5-dichloropyridin-4-yl)piperidin-4-yl)methanol E61

General procedure C was followed using 3,4,5-trichloropyridine (50 mg,0.27 mmol), piperidin-4-ylmethanol (35 mg, 0.30 mmol), triethylamine (76μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flashcolumn chromatography on silica gel (hexane, EtOAc, 85:15) to furnishthe title compound as white solid (51 mg, 71%), LC-MS (ESI, 3.5 min)R,2.49 min, m/z 261 (100%, [M+H]⁺); m/z (ESI) C₁₁H₁₃Cl₂N₂O requires261.0556 found [M+H]⁺ 261.0558; HPLC R, 6.68 min, 100%.

Example 62(R,S)-1-(3-chloro-5-phenylpyridin-4-yl)pyrrolidine-3-carbonitrile E62

General procedure D was followed using(R,S)-1-(3,5-dichloropyridin-4-yl)pyrrolidine-3-carbonitrile 14 (25 mg,0.10 mmol), benzene boronic acid (15 mg, 0.12 mmol),tetrakis(triphenylphosphine)palladium(0) (6 mg, 5 mol %), 0.5 M sodiumcarbonate (0.29 mL, 0.14 mmol) and acetonitrile (1 mL) for 30 min. Thecrude product was purified preparative hplc (CH₃CN, H₂O, gradient 1:9 to9:1) to furnish the title compound as white solid (8 mg, 27%), LC-MS(ESI, 3.5 min)R, 1.64 min, m/z 284 (100%, [M+Na]⁺).

Example 63 ethyl1-(3,5-dichloropyridin-4-yl)-4-methylpiperidine-4-carboxylate E63

To a solution of ethyl N-Boc-4-methylpiperidine-4-carboxylate (130 mg,0.47 mmol) in CH₂Cl₂ (8 mL) was added trifluoroacetic acid (0.86 mL, 11mmol) and the reaction stirred at r.t. for 2 hr before evaporation andaziotrope with toluene (2×25 ml). The crude was dissolved in NMP (4.3ml) and 3,4,5-trichloropyridine (135 mg, 0.74 mmol) was added followedby triethylamine (0.42 mL, 3.0 mmol) and the mixture was heated in amicrowave reactor at 220° C. for 60 min. The mixture was poured into asaturated solution of sodium hydrogen carbonate (50 mL) and extractedwith EtOAc (2×100 mL). The combined organic extracts were washed withwater (2×50 mL), brine (50 mL), dried (MgSO₄) and concentrated underreduced pressure to give a crude pale brown/orange oil (175 mg). Thecrude product was purified by flash column chromatography on silica gel(cyclohexane, EtOAc, 99:1-88:12, biotage 25+S) to furnish the titlecompound as a clear colourless oil (85 mg, 56%), LC-MS (ESI, 4 min)R_(t) 3.36 min, m/z 317 (100%, [M+H]⁺); m/z (ESI) C₁₄H₁₈N₂O₂Cl₂ requires316.0745, found [M+H]⁺ 316.0745.

Example 64(R,S)-1-(3-chloro-5-phenylpyridin-4-yl)pyrrolidine-3-carboxamide E64

General procedure D was followed using(R,S)-1-(3,5-dichloropyridin-4-yl)pyrrolidine-3-carboxamide E21 (23 mg,0.088 mmol), benzene boronic acid (13 mg, 0.11 mmol) andtetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile(1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. Thecrude product was purified by preparative tlc on silica gel (CH₂Cl₂,MeOH, 10:1), to give a white solid (14 mg), followed by preparative hplc(H₂O, MeCN, gradient 90:10 to 10:90 over 30 min) to furnish the titlecompound as a white solid, LC-MS (ESI, 3.5 min) R_(t) 1.32 min, m/z 302(100%, [M+H]⁺); m/z (ESI) C₁₆H₁₇ClN₃O requires 302.1055 found [M+H]⁺302.1047.

Example 65 1-(5-chloro-3,4′-bipyridin-4-yl)piperidine-4-carboxamide E65

General procedure D was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088mmol), pyridin-4-yl boronic acid (12 mg, 0.11 mmol),tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile(1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. Thecrude product was purified by preparative tlc on silica gel (CH₂Cl₂,MeOH, 10:1) to furnish the title compound as a white solid (5 mg, 18%),LC-MS (ESI, 3.5 min) R_(t) 1.10 min, m/z 317 (100%, [M+H]⁺); m/z (ESI)C₁₆H₁₈ClN₄O requires 317.1164 found [M+H]⁺ 317.1160.

Example 66 1(3-cyclopropylpyridin-4-yl)piperidine-4-carboxamide E66

General procedure D was followed using1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (25 mg, 0.088 mmol),cyclopropyl boronic acid (9.4 mg, 0.44 mmol),tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), 0.5 M sodiumcarbonate (0.25 mL, 0.12 mmol) and acetonitrile (1 mL) for 50 min. Thecrude product was purified by preparative tlc on silica (CH₂Cl₂, MeOH10:1) to furnish the title compound as a white solid (4 mg, 19%), LC-MS(ESI, 3.5 min) R_(t) 0.97 min, m/z 246 (100%, [M+H]⁺); m/z (ESI)C₁₄H₁₉N₃O requires 246.1601 found [M+H]⁺ 246.1596.

Example 67 1-(3-(1H-pyrazol-4-yl)pyridin-4-yl)piperidine-4-carboxamideE67

General procedure 0 was followed using1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (25 mg, 0.088 mmol),1H-pyrazol-4-boronic acid pinnacol ester (21 mg, 0.11 mmol),tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), 0.5 M sodiumcarbonate (0.25 mL, 0.12 mmol) and acetonitrile (1 mL) for 50 min. Thecrude product was purified by preparative hplc (H₂O, MeCN, 95:5) tofurnish the title compound as a white solid (11 mg, 46%), m/z (ESI)C₁₄H₁₈N₅O requires 272.1506 found [M+H]⁺ 272.1509.

Example 68 1-(3-phenylpyridin-4-yl)piperidine-4-carboxamide E68

To a mixture of 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (20mg, 0.070 mmol), phenylboronic acid (17 mg, 0.14 mmol) andtetrakis(triphenylphosphine)palladium(0) (8 mg, 10 mol %) in toluene(1.5 mL) was added a 0potassium phosphate (45 mg, 0.21 mmol). Themixture was heated at 170° C. in a microwave reactor for 45 min, thenpoured into a saturated solution of sodium hydrogen carbonate (25 mL).The mixture was extracted with EtOAc (2×20 mL) and the combined organicextracts were washed with brine (25 mL), dried (MgSO₄) and the solventwas removed under reduced pressure. The crude product was purified byflash column chromatography on silica gel (CH₂Cl₂, MeOH, 95:5) tofurnish the title compound as a white solid (5 mg, 25%), LC-MS (ESI, 3.5min) R_(t) 1.28 min, m/z 282 (100%, [M+H]⁺), m/z (ESI) C₁₇H₂₀N₃Orequires 282.1601 found [M+H]⁺ 282.1597.

Example 69 (1(3,5-dichloropyridin-4-yl)piperidin-4-yl)methanamine E69

To a solution of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23(30 mg, 0.11 mmol) in THF (2 mL), at 0° C., was added a 1M solution ofborane THF complex in THF (11.1 mL, 1.1 mmol). The reaction was stirredfor 1 hour before warming to r.t. and stirring for a further 18 hr. Tothe reaction was added 2M HCl (2 ml), the mixture diluted with water (20ml) and extracted with EtOAc (2×20 mL) and the combined organic extractswere washed with brine (25 mL). The combined aqueous extracts werebasified with saturated sodium hydrogen carbonate and then extractedwith EtOAc (2×20 mL). The combined organic extracts were washed withbrine (20 mL), dried (MgSO₄) and concentrated under reduced pressure togive a crude colourless oil (8 mg). The crude product was purified byflash column chromatography on silica gel (CH₂Cl₂, MeOH, 97:3 to CH₂Cl₂,1 M methanolic NH₃, 9:1) to furnish the title compound, LC-MS (ESI, 3.5min) H_(t) 1.45 min, m/z 260 (91%, [M+H]⁺).

Example 701-(3-chloro-5-(4-dimethylamino)pyridin-4-yl)piperidine-4-carboxamide E70

General procedure D was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088mmol), (4-dimethylamino)benzene boronic acid (17 mg, 0.11 mmol),tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile(1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. Thecrude product was purified by preparative tlc on silica gel (CH₂Cl₂,MeOH, 10:1) followed by preparative hplc (CH₃CN, H₂O, gradient 1:9 to9:1) to furnish the title compound as a white solid (4 mg, 13%), LC-MS(ESI, 3.5 min)R, 1.54 min, m/z 359 (100%, [M+H]⁺); m/z (ESI)C₁₉H₂₄Cl₃N₄O requires 359.1633 found [M+H]⁺ 359.1633.

Example 711-(3-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyridine-4-yl)piperidine-4-carboxamideE71

General procedure D was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088mmol), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (20 mg, 0.11mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %),acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for30 min. The crude product was purified by preparative tlc on silica gel(CH₂Cl₂, MeOH, 10:1) to furnish the title compound as a white solid (8mg, 29%), LC-MS (ESI, 3.5 min)R, 1.20 min, m/z 320 (100%, [M+H]⁺): m/z(ESI) C₁₅H₁₉ClN₅O requires 320.1273 found [M+H]⁺320.1272.

Example 721-(5-chloro-6′-(dimethylamino)-3,3′-bipyridin-4-yl)piperidine-4-carboxamideE72

General procedure E was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (50 mg, 0.18mmol), 2-(N,N-dimethylamino)pyridine-5-boronic acid 2HCl salt (55 mg,0.23 mmol), tetrakis(triphenylphosphine)palladium(0) (11 mg, 5 mol %),acetonitrile (2 mL) and 0.5 M sodium carbonate (1.3 mL, 0.66 mmol). Thecrude product was purified by flash column chromatography on silica gel(CH₂Cl₂, EtOH, 96:4-82:18, biotage 25+S) followed by preparative tlc(CH₂Cl₂, MeOH, 9:1) to furnish the title compound as an off white solid(6 mg, 9%), LC-MS (ESI, 4 min)R, 1.28 min, m/z 360 (100%, [M+H]⁺); m/z(ESI) C₁₇H₂₂N₅OCl requires 359.1513, found [M+H]⁴ 359.1511.

Example 73 N-(1-(3,5-dichloropyridin-4-yl)piperidin-4-yl)acetamide E73

General procedure C was followed using 3,4,5-trichloropyridine (50 mg,0.27 mmol), 4-acetamidopiperidine (43 mg, 0.30 mmol), triethylamine (76μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flashcolumn chromatography on silica gel (hexane, EtOAc, MeOH, 1:1:0.05) tofurnish the title compound as white solid (7 mg, 9%), LC-MS (ESI, 3.5min) R_(t) 2.25 min; m/z (ESI) C₁₂H₁₆Cl₂N₃O requires 288.0665 found[M+H]⁺ 288.0664; HPLC R_(t) 5.98 min, 100%.

Example 741-(3-chloro-5-(4-methoxyphenyl)pyridin-4-yl)pyrrolidine-3-carboxamideE74

General procedure D was followed using1-(3,5-dichloropyridin-4-yl)pyrrolidine-3-carboxamide E21 (23 mg, 0.088mmol), 4-methoxybenzene boronic acid (13 mg, 0.11 mmol),tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile(1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. Thecrude product was purified by preparative tlc on silica gel (CH₂Cl₂,MeOH, 10:1) to give impure title compound as a white solid (15 mg).Further purification by preparative hplc (H₂O, MeCN, gradient 90:10 to10:90 over 30 min) furnished the title compound as a white solid, LC-MS(ESI, 3.5 min) R_(t) 1.40 min, m/z 332 (100%, [M+H]⁺); m/z (ESI, 3.5min) C₁₇H₁₈ClN₃NaO₂ requires 354.0980 found [M+Na]⁺ 354.0980

Example 75 1-(5-chloro-3,3′-bipyridin-4-yl)piperidine-4-carboxamide E75

General procedure D was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088mmol), pyridin-3-yl boronic acid (12 mg, 0.11 mmol),tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile(1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. Thecrude product was purified by preparative tlc on silica gel (CH₂Cl₂,MeOH, 10:1) to furnish the title compound as a white solid (7 mg, 25%),LC-MS (ESI, 3.5 min) R_(t) 1.06 min, m/z 317 (100%, [M+H]⁺); m/z (ESI)C₁₆H₁₈ClN₄O requires 317.1164 found [M+H]⁺ 317.1161.

Example 761-(3-chloro-5-(2-methoxypyrimidin-5-yl)pyridin-4-yl)piperidine-4-carboxamideE76

General procedure E was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (75 mg, 0.27mmol), 2-methoxypyrimidine-5-boronic acid (53 mg, 0.34 mmol),tetrakis(triphenylphosphine)palladium(0) (16 mg, 5 mol %), acetonitrile(3 mL) and 0.5 M sodium carbonate (0.77 mL, 0.38 mmol). The crudeproduct was purified by flash column chromatography on silica gel(CH₂Cl₂, EtOH, 96:4-82:18, biotage 25+S) to furnish the title compoundas an off white solid (20 mg, 21%), along with recovered1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide as a white solid(32 mg, 43% RSM), LC-MS (ESI, 4 min) R_(t) 1.76 min, m/z 348 (100%,[M+H]⁺); m/z (ESI) C₁₆H₁₈N₅O₂Cl requires 347.1149, found [M+H]⁺347.1147.

Example 771-(3-chloro-5-(3,4-difluorophenyl)pyridin-4-yl)piperidine-4-carboxamideE77

General procedure D was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088mmol), 3,4-difluorobenzene boronic acid (17 mg, 0.11 mmol),tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile(1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. Thecrude product was purified by preparative tlc on silica gel (CH₂Cl₂,MeOH, 10:1), to give impure title compound as a white solid (16 mg)followed by preparative hplc (CH₃CN, H₂O, gradient 1:9 to 9:1) tofurnish the title compound as a white solid, LC-MS (ESI, 3.5 min) R_(t)1.91 min, m/z 352 (100%, [M+H]⁺); m/z (ESI) C₁₇H₁₆ClF₂N₃O requires352.1023 found [M+H]⁺ 352.1017.

Example 781-(3-chloro-5-(1H-pyrazol-4-yl)pyridin-4-yl)piperidine-4-carboxamide E78

General procedure D was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088mmol), I H-pyrazole-4-boronic acid pinacol ester (12 mg, 0.11 mmol),tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile(1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. Thecrude product was purified by preparative tlc on silica gel (CH₂Cl₂,MeOH, 10:1) to furnish the title compound as a white solid (18 mg, 67%),LC-MS (ESI, 3.5 min) R_(t) 1.06 min, m/z 306 (100%, [M+H]⁴); m/z (ESI)C₁₄H₁₇ClN₅O requires 306.1116 found [M+H]⁺ 306.1114.

Example 791-(3-chloro-5-(thiophen-2-yl)pyridin-4-yl)piperidine-4-carboxamide E79

General procedure E was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (75 mg, 0.27mmol), 2-thiophene boronic acid (44 mg, 0.34 mmol),tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol),acetonitrile (3 mL) and 0.5 M sodium carbonate (0.77 mL, 0.38 mmol). Thecrude product was purified by flash column chromatography on silica gel(CH₂Cl₂, EtOH, 96:4-80:20, biotage 25+S) to yield the a mixture ofstarting material and product (50 mg, 2:5), along with dehalogenatedmonochioro starting material (7 mg, 11%). The product/starting materialmixture was further purified by preparative hplc (CH₃CN, H₂O, gradient1:9 to 9:1, 15 min) to furnish the title compound (9 mg, 10%) as a clearcolourless oil, along with recovered1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (30 mg, 40%) as awhite solid, LC-MS (ESI, 4 min) R_(t) 2.31 min, m/z 322 (100%, [M+H]⁺);m/z (ESI) C₁₅H₁₆N₃OSCl requires 321.0703, found [M+H]⁺ 321.0700.

Example 80 1-(3-bromo-5-chloropyridin-4-yl)piperidine-4-carboxamide E80

To a solution of 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36(100 mg, 0.35 mmol) in DMF (7.00 mL) was added N-chlorosuccinimide (94mg, 0.70 mmol). The reaction was heated to 80° C. and stirred for 8hours before partitioning between EtOAc and water (100 ml each), theseparated organic layer was washed with water (2×75 ml), brine (20 mL),dried (MgSO₄) and concentrated under reduced pressure to give a crudeclear pale yellow oil (82 mg). The crude product was purified by flashcolumn chromatography on silica gel (CH₂Cl₂, EtOH, 98:2-84:16, biotage25+S) followed by flash column chromatography on silica gel (CH₂Cl₂,EtOH, 96:4-82:18, biotage 14+M) to give a mixture of title compound and1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide by-product as awhite solid (20 mg). The mixture was further purified by preparativehplc (MeOH, H₂O, 9:20, 25 min) to furnish the title compound as a whitesolid, LC-MS (ESI, 4 min) R_(t) 2.46 min, m/z 320 (100%, [M+H]⁺); m/z(ESI) C₁₁H₁₃N₃OClBr requires 316.9931, found [M+H]⁺ 318.0003.

Example 811-(3-(4-trifluoromethylphenyl)pyridin-4-yl)piperidine-4-carboxamide E81

General procedure D was followed using1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (25 mg, 0.088 mmol),4-trifluoromethyphenyllboronic acid (20 mg, 0.11 mmol),tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), 0.5 M sodiumcarbonate (0.25 mL, 0.12 mmol) and acetonitrile (1 mL) for 50 min. Thecrude product was purified by preparative tlc on silica gel (CH₂Cl₂,MeOH, 10:1) to furnish the title compound as a white solid (28 mg, 91%),LC-MS (ESI, 3.5 min)R, 1.51 min, m/z 350 (100%, [M+H]⁺); m/z (ESI)C₁₈H₁₉F₃N₃O requires 350.1475 found [M+H]⁺ 350.1478.

Examples 82 and 831-(3-bromo-5-o-tolylpyridin-4-yl)piperidine-4-carboxamide E82 and1-(3,5-dio-tolylpyridin-4-yl)piperidine-4-carboxamide E83

To a solution of 1-(3,5-dibromopyridin-4-yl)piperidine-4-carboxamide E27(50 mg, 0.14 mmol), o-tolylboronic acid (77 mg, 0.56 mmol) and potassiumphosphate (0.20 g, 0.96 mmol) in toluene (4 mL) was addedtetrakis(triphenylphosphine)palladium(0) (18 mg, 10 mol %). The mixturewas heated at 170° C. in a microwave reactor for 45 min, then pouredinto a saturated solution of sodium hydrogen carbonate (25 mL). Themixture was extracted with EtOAc (2×25 mL) and the combined organicextracts were washed with water (25 mL), brine (25 mL), dried (MgSO₄)and the solvent was removed under reduced pressure. The crude productwas purified by flash column chromatography on silica gel (CH₂Cl₂, MeOH,98:2) to yield impure title compound as a white solid (23 mg). Furtherpurification by preparative hplc furnished both title compounds as whitesolids.

1-(3-bromo-5-o-tolylpyridin-4-yl)piperidine-4-carboxamide E82

(13 mg, 24%), LC-MS (ESI, 3.5 min) R_(t) 1.85 min, m/z 376 (100%,[M+H]⁺); m/z (ESI) C₂₅H₂₈N₃O requires 374.0863 found [M+H]⁺ 374.0860.

1-(3,5-dio-tolylpyridin-4-yl)piperidine-4-carboxamide E83

(3.3 mg, 6%), LC-MS (ESI, 3.5 min)R, 1.66 min, m/z 386 (100%, [M+H]⁺);m/z (ESI) C₁₈H₂₁BrN₃O requires 386.2227 found [M+H]⁺ 386.2225.

Example 841-(3-chloro-5-(3,4,5-trimethoxyphenyl)pyrimidin-4-yl)piperidine-4-carboxamideE84

General procedure D was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088mmol), 3,4,5-trimethoxyphenyllboronic acid (22 mg, 0.11 mmol),tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), 0.5 M sodiumcarbonate (0.25 mL, 0.12 mmol) and acetonitrile (1 mL) for 30 min. Thecrude product was purified by preparative tlc on silica gel (CH₂Cl₂,MeOH, 10:1) to give impure title compound as a colourless oil (17 mg).Further purification by preparative hplc furnished the title compound,LC-MS (ESI, 3.5 min) R_(t) 1.71 min, m/z 406 (100%, [M+H]⁺); m/z (ESI)C₂₀H₂₅ClN₃O₄ requires 406.1528 found [M+H]⁺ 406.1526.

Example 85 1-(5-(4-methoxyphenyl)pyrimidin-4-yl)piperidine-4-carboxamideE85

General procedure D was followed using1-(5-bromopyrimidin-4-yl)piperidine-4-carboxamide E29 (11 mg, 0.039mmol), 4-methoxyphenylboronic acid (7 mg, 0.046 mmol),tetrakis(triphenylphosphine)palladium(0) (2.5 mg, 5 mol %), 0.5 M sodiumcarbonate (0.11 mL, 0.054 mmol) and acetonitrile (1 mL) for 30 min. Thecrude product was purified by preparative tlc on silica gel (CH₂Cl₂,MeOH, 10:1) to furnish the title compound as a white solid (5 mg, 41%),LC-MS (ESI, 3.5 min) R_(t) 1.33 min, m/z 312 (100%, [M+H]⁺)

Example 86 1-(3-chloro-5-phenylpyridin-4-yl)piperidine-4-carbonitrileE86

General procedure D was followed using1-(3,5-dichloropyridin-4-yl)piperidine-4-carbonitrile E48 (100 mg, 0.39mmol), phenylboronic acid (57 mg, 0.47 mmol),tetrakis(triphenylphosphine)palladium(0) (22 mg, 5 mol %), 0.5 M sodiumcarbonate (1.1 mL, 0.55 mmol) and acetonitrile (3.5 mL) for 45 min. Thecrude product was purified by preparative hplc (H₂O, MeCN, 90:10-10:90,30 min) to furnish the title compound (25 mg, 22%), LC-MS (ESI, 3.5 min)R_(t) 2.24 min, m/z 298 (100%, [M+H]⁺).

Example 87 1-(3-chloro-5-phenylpyridin-4-yl)piperidine-4-carboxylic acidE87

A solution of 1-(3-chloro-5-phenylpyridin-4-yl)piperidine-4-carbonitrileE86 (16 mg, 0.054 mmol) was heated in 6M hydrochloric acid (1 mL) for 2hours at 100° C. The reaction was concentrated under reduced pressureand purified on an SCX-2 cartridge (MeOH, followed by 0.5 M NH₃ inMeOH). The crude product was purified by preparative tlc on silica gel(CH₂Cl₂, MeOH, 10:1) to furnish the title compound (5 mg, 30%), LC-MS(ESI, 4 min) R_(t) 2.13 min, m/z 317 (100%, M+H]⁺).

Example 88 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxylic acid E88

A solution of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carbonitrile E48(25 mg, 0.097 mmol) was heated in 6M hydrochloric acid (2 mL) for 3hours at 100° C. The reaction was concentrated under reduced pressureand purified on an SCX-2 cartridge (MeOH, followed by 0.5 M NH₃ inMeOH). The crude product (16 mg) was purified by preparative tlc onsilica gel (CH₂Cl₂, MeOH, 10:1) to furnish the title compound, LC-MS(ESI, 4 min) R_(t) 2.83 min, m/z 275 (100%, M+Hr); m/z (ESI)C₁₁H₁₂Cl₂N₂O₂ requires 275.0349 found [M+H]⁺275.0349.

Example 89 benzyl2-(1-(3-chloro-5-phenylpyridin-4-yl)piperidine-4-carboxamido)ethylcarbamateE89

General procedure D was followed usingbenzyl-2-(1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamido)ethylcarbamate 11 (105 mg, 0.23 mmol), phenylboronic acid (34 mg, 0.28 mmol),tetrakis(triphenylphosphine)palladium(0) (13 mg, 5 mol %), 0.5 M sodiumcarbonate (0.65 mL, 0.33 mmol) and acetonitrile (2.5 mL) for 45 min. Thecrude product was purified by preparative tlc on silica gel (CH₂Cl₂,MeOH, 10:1) to give impure title compound (32 mg). Further purificationby preparative hplc furnished the title compound, LC-MS (ESI, 3.5 min)R_(t) 2.43 min, m/z 494 (100%, [M+H]⁺).

Example 90N-(2-aminoethyl)-1-(3-chloro-5-phenylpyridin-4-yl)piperidine-4-carboxamideE90

To a solution ofbenzyl-2-(1-(3-chloro-5-phenylpyridin-4-yl)piperidine-4-carboxamido)ethylcarbamateE89 (39 mg, 0.079 mmol) in CH₂Cl₂ (2 mL), at 0° C., was added TMSI (34μL, 0.24 mmol). The reaction was warmed to r.t. over 3 hours and thenconcentrated under reduced pressure and purified on an SCX-2 cartridge(MeOH, followed by 0.5 M NH₃ in MeOH) to furnish the title compound (23mg, 81%), LC-MS (ESI, 3.5 min) R_(t) 1.33 min, m/z 359 (40%, [M+H]⁺);m/z (ESI) C₁₉H₂₄ ClN₄O requires 359.1623 found [M+H]⁺359.1633.

Example 911-(3,5-bis(4-methoxyphenyl)pyridin-4-yl)piperidine-4-carboxamide E91

General procedure D was followed using1-(3,5-dibromopyridin-4-yl)piperidine-4-carboxamide E27 (50 mg, 0.14mmol), 4-methoxyphenylboronic acid (25 mg, 0.15 mmol),tetrakis(triphenylphosphine)palladium(0) (8 mg, 5 mol %), acetonitrile(1.4 mL) and 0.5 M sodium carbonate (0.27 mL, 0.16 mmol) for 30 min. Thecrude product was purified by flash column chromatography on silica gel(CH₂Cl₂, MeOH, 98:2) to furnish the title compound as a white solid (39mg), LC-MS (ESI, 3.5 min)R, 1.68 min, m/z 418 (100%, [M+H]⁺).

Example 92 Activity Assay

Inhibitory activity of the Wnt pathway was assessed using a luciferasereporter cell based assay. A luciferase reporter cell line was developedin HEK293 cells, which contained an estrogen receptor-DSH (ER-DSH)construct and a TCF-luciferase-IRES-GFP construct.

A high-throughput assay was performed by inducing TCF-dependenttranscription in the ER-DSH HEK293 cell line by the addition of estrogen(2 μM) resulting in at least a 14-fold increase in reporter activitymeasured at 24 hours.

Subsequent primary and secondary deconvolution assays were used toevaluate the compounds. Firstly, compounds were tested for inhibitoryactivity in HEK293 cells transiently transfected with a TCF-luciferasereporter plasmid alone or in combination with an ER-inducible DSHplasmid. Induction of the pathway was brought about with eitherestradiol or BIO. A TK-Renilla luciferase plasmid was used as aco-transfected control to identify compounds with specificity for Wntsignalling compared to general transcription.

Particular compounds of the invention possess and IC50 in theabove-mentioned luciferase assay of less than 10 μM. Preferred compoundshave an IC50 of less than 1 μM and most preferred compounds have an IC50of less than 0.5 μM.

Illustrative activity values for particular compounds of the inventionin the Luciferase reporter assay described above are shown in Table Abelow:

TABLE A Example/Com- IC50 in Luciferase reporter assay (ER-DSH HEK293pound Number cells) assay described in Example 92 (μM) E1 12.6 E2 30.0E4 0.17 E9 12.1 E12 22.9 E13 7.0 E21 0.76 E27 0.21 E29 16.2 E33 5.0 E357.66 E37 1.64 E43 0.032 E47 0.44 E50 0.11 E59 3.43 E60 0.033 E65 0.44E68 1.15 E74 0.26 E85 1.58 E86 0.09 E87 0.74

Compounds were then further tested in similar assays in which thepathway was induced by constitutive expression of DN-LRP (a component ofthe Wnt receptor), Ax-2 (a dominant negative form of axin), DN-β-catenin(a stabilised form of β-catenin) and VP16-TCF (a TCF transcriptionfactor active in the absence of β-catenin).

The growth inhibitory activity of compounds was also determined againsta small panel of human colorectal cell lines (HCT116, HT29, and SW480).

Certain compounds were found to have a GI₅₀ against the HT29 cell lineof less than 100 μM and an IC₅₀ against the Luciferase reporter vectorof less than 100 μM.

1. A compound of the formula (I):

wherein X and Y are each independently CH, C(R⁴) or N; W is C(R⁴); Z isC(R⁶) or N; R¹ and R² are each independently hydrogen or C₁₋₆ alkyl; orR¹ and R² taken together with the carbon atom to which they are attachedmay form a 5- or 6-membered carbocycle or heterocycle, either of whichis optionally substituted with 1, 2, 3, 4 or 5 R^(a); R³ and R⁴ are eachindependently a group selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, carbocyclyland heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4or 5 R^(a); when Z is N, R⁵ is R⁷, —C(O)R⁷, —C(O)OR⁷—, —S(O)_(l)R⁷,—C(O)N(R⁷)R⁸, —C(S)N(R⁷)R⁸—, —S(O)_(l)N(R⁷)R⁸ or heterocyclyl optionallysubstituted with 1, 2, 3, 4 or 5 R^(a); when Z is C(R⁶), R⁵ is H, CN,C(O)OH, —C(O)R⁷, —C(O)OR⁷—, —S(O)_(l)R⁷, —N(R⁶)R⁷, —C(O)N(R⁷)R⁸,—C(S)N(R⁷)R⁸—, —S(O)_(l)N(R⁷)R⁸, —N(R⁷)C(O)R⁸, —N(R⁷)S(O)_(l)R⁸ or aC₁₋₆ alkyl or heterocyclyl group which is optionally substituted with 1,2, 3, 4 or 5 R^(a); R⁶ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —OH, R⁵,(CH₂)_(m)R⁵ or —N(R⁷)R⁸; R⁷ and R⁸ are each independently hydrogen or agroup selected from C₁₋₆ alkyl optionally containing 1, 2 or 3heteroatoms selected from N, O and S, carbocyclyl and heterocyclyl, anyof which is optionally substituted with 1, 2, 3, 4 or 5 R^(a); or R⁷ andR⁸ may be linked so that, together with the atoms to which they areattached, they form a 5- or 6-membered heterocycle which is optionallysubstituted with 1, 2, 3, 4 or 5 R^(a); each R^(a) is independentlyselected from halogen, trifluoromethyl, cyano, oxo, nitro, —OR^(b),—C(O)R^(b), —C(O)OR^(b), —OC(O)R^(b), —S(O)_(l)R^(b), —N(R^(b))R^(c),—N(R^(b))C(O)R^(c), —C(O)N(R^(b))R^(c), —S(O)_(l)N(R^(b))R^(c) andR^(d); R^(b) and R^(c) are each independently hydrogen or R^(d); R^(d)is selected from hydrocarbyl (e.g. C₁₋₆alkyl), carbocyclyl,carbocyclyl-C₁₋₆alkyl, and heterocyclyl, each of which is optionallysubstituted with 1, 2, 3, 4 or 5 substituents independently selectedfrom halogen, cyano, amino, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy; l is 0, 1or 2; and m and n are each independently 1, 2 or 3; or apharmaceutically acceptable salt or N-oxide thereof.
 2. A compoundaccording to claim 1, which is of the formula (II):

wherein T is a bond or —CH₂—.
 3. A compound according to claim 1,wherein X and Y are each CH. 4-5. (canceled)
 6. A compound according toclaim 1, wherein R³ is a group selected from C₁₋₆ alkyl, aryl orheteroaryl, any of which is optionally substituted with 1, 2, 3, 4 or 5R^(a).
 7. A compound according to claim 6, wherein R³ is a groupselected from C₁-C₆ alkyl, phenyl, pyrazolyl, triazolyl, oxazolyl,isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl and thiophenyl, any ofwhich is optionally substituted with 1, 2, 3, 4 or 5 R^(a).
 8. Acompound according to claim 1, wherein Z is C(R⁶).
 9. A compoundaccording to claim 8, wherein R⁶ is hydrogen, methyl, or aniline.
 10. Acompound according to claim 1, wherein R⁵ is —C(O)NH₂, CO₂H, CN orheterocyclyl. 11-12. (canceled)
 13. A compound which is selected fromany one of the following:4-(3-methylpyridin-4-yl)cyclohexanecarboxamide;4-(3,5-dimethylpyridin-4-yl)cyclohexanecarboxamide;1-(5-methylpyrimidin-4-yl)piperidine-4-carboxamide;1-(5-phenylpyrimidin-4-yl)piperidine-4-carboxamide;1-(3-(4-methoxyphenyl)pyridin-4-yl)piperidine-4-carboxamide;1-(3-(thiophen-2-yl)pyridin-4-yl)piperidine-4-carboxamide;1-(3,5-diphenylpyridin-4-yl)piperidine-4-carboxamide;1-(3-(3,5-dimethylisoxazol-4-yl)pyridin-4-yl)piperidine-4-carboxamide;1-(3-(thiophen-3-yl)pyridin-4-yl)piperidine-4-carboxamide;1-(3-cyclopropylpyridin-4-yl)piperidine-4-carboxamide;1-(3-(1H-pyrazol-4-yl)pyridin-4-yl)piperidine-4-carboxamide;1-(3-phenylpyridin-4-yl)piperidine-4-carboxamide;1-(3,5-dio-tolylpyridin-4-yl)piperidine-4-carboxamide;1-(5-(4-methoxyphenyl)pyrimidin-4-yl)piperidine-4-carboxamide;1-(3,5-bis(4-methoxyphenyl)pyridin-4-yl)piperidine-4-carboxamide; or apharmaceutically acceptable salt or N-oxide thereof. 14-15. (canceled)16. A compound of the formula (I) as defined in claim 1 with the provisothat R⁴ is not an optionally substituted imidazolyl group. 17.(canceled)
 18. A pharmaceutical formulation comprising a compound ofclaim 1 and a pharmaceutically acceptable carrier or excipient. 19.(canceled)
 20. A method for the treatment, prevention or delaying theprogression of cancer in a subject, which comprises administering atherapeutically effective amount of a compound of formula (I) as definedin claim 1.